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MAY PROVIDE THE BASIS FOR THE
DEVELOPMENT OF NEW THERAPEUTIC
APPROACHES TO TREAT THIS
CONDITION AND ALSO REDUCE
MORTALITY, MORBIDITY AND
DISABILITY ASSOCIATED WITH
CHRONIC LUNGS.
AS MOST OF YOU PROBABLY KNOW,
THE UNITED STATES SPENDS MORE
THAN 25 BILLION, MAKE THAT
BILLION WITH A B, DOLLARS,
ANNUALLY ON WOUND CARE.
IMPROVED TECHNIQUES FOR
PROMOTING HEALING OF WOUNDS HAVE
GREAT IMPACT ON HEALTH CARE
COSTS AS WELL.
THE TITLE OF DR. MARJANA
TOMIC-CANIC'S PRESENTATION IS
WIZZ ADD REOF TISSUE REPAIR AND
REGENERATION OF SKIN CELLS WHEN
THE MANAGE SICK ALL ABOUT GONE.
PLEASE WELCOME ME IN JOINING
DR. MARJANA TOMIC-CANIC.
(APPLAUSE)
>> GOOD AFTERNOON, EVERYONE.
CAN YOU HEAR ME WELL.
IT IS REALLY A GREAT PLEASURE TO
BE HERE TODAY AND I WANT TO
THANK THE NURSING RESEARCH FOR
NOMINATING ME FOR THIS LECTURE
AND ORGANIZERS FOR GIVING ME THE
OPPORTUNITY TO SHARE TODAY WITH
YOU OUR RESEARCH AND THE
APPROACHES TO HEAL WOUNDS.
AND IF IT WASN'T FOR POETRY AND
INFLUENCE OF MY DAUGHTER WHO IS
A BIG HARRY POTTER FAN AND MY
SON WHO LOVES GRAPHIC DESIGN, MY
TITLE WOULD HAVE BEEN SLIGHTLY
SIMPLER AND AND WOULD READ
CELLULAR AND MOLECULAR WOUND
HEALING IN PATHOGENESIS.
THAT'S WHAT I WILL BE TALKING
ABOUT TODAY.
SO THE REVIEW OF THE LECTURE
WILL BE A BRIEF INTRODUCTION OF
THE SKIN BIOLOGY AND BASIC CELLS
AND WOUND HEALING AND LI DIVIDE
THE TALK INTO TWO PARTS, THE
FIRST WILL BE LESSONS LEARNED
FROM PATIENTS WHERE WE TOOK THE
APPROACH OF TAKING THE BIOPSIES
FROM CHRONIC PATIENTS AND TRYING
TO ANALYZE BOTH CELLULAR AND
MOLECULAR ASPECTS OF INHIBITION
OF HEALING FROM THE MANY LESSONS
FROM BASIC AND MOLECULAR
CELLULAR MECHANISMS.
THEN THE SECOND PART OF THE TALK
WILL BE FLIPPING THE DECIDE
TRYING TO GO FROM
BENCH-TO-BEDSIDE AND APPLY WHAT
WE LEARNED IN PRACTICAL
SETTINGS.
AND SO, THE PRIMARY FUNCTION OF
SKIN, I HAVE BEEN FASCINATED
WITH THIS ORGAN EVER SINCE I
STARTED MY GRADUATE SCHOOL, IS
THAT OBVIOUSLY THE GOAL OF SKIN
EXIST SENSE BARRIER FORMATION
AND ITS MAINTENANCE.
AND THAT IS ACHIEVED THROUGH
REALLY A REMARKABLE PERPETUAL
PROCESS IF YOU WANT, WHERE BASAL
KERATIN OCYTES WHERE ARE THE --
WHICH ARE THE MOST PROLIFERATIVE
POTENTIAL COMPARTMENTS OF SKIN,
DIVIDE AND THEN ONE CELL WILL
TURN ON AND START
DIFFERENTIATING COMPLETING THIS
SORT OF PROCESS OF TERMINAL
DIFFERENTIATION IN THE BARRIER
FORMATION.
SO THIS PROCESS, THE KERATIN
SIGHTS WILL LOSE THEIR NUCLEI,
CROSSLINK THEIR PROTEINS AND
DIE.
AND TOGETHER WITH LIPIDS WILL
FORM THE BARRIER AS WE SEAT
FORTIFIED LAYER.
HOW IS THIS REALLY ACHIEVED?
OBVIOUSLY WE HAVE TO THANK
EPIDERMAL STEM CELLS FOR IT.
THEY RESIDE, THERE ARE TWO
COMPARTMENTS, ONE IS BASAL LAYER
OF EP DEMIS WHERE THEY
SYMMETRICALLY DIVIDE AND START
DIFFERENTIATING TERMINALLY AND
THEN THE SECOND COMPARTMENT THAT
IS EQUALLY IMPORTANT FOR WOUND
HEALING, RESIDES IN THE AREA OF
THE HAIR FOLLICLE.
NORMALLY, IN A STEADY STATE,
THESE CELLS DON'T PARTICIPATE
MUCH IN BIOLOGY OF EPIDERMIS
UNLESS THE WOUND HAPPENS.
THEY ARE RESPONSIBLE FOR
FORMATION OF HAIR FOLLICLE AND
THE CYCLING OF HAIR AND BIOLOGY
OF THE HAIR FOLLICLE.
BUT, IF THE WOUND HAPPENS, THE
STEM CELLS WILL START MIGRATING
IN THE EPIDERMIS AND AGE TO THE
WOUND HEALING PROCESS AND THAT
BECOMES VERY IMPORTANT FOR WHAT
I'M GOING TALK ABOUT TODAY.
SO, CLEARLY SKIN HAS THIS
ENORMOUS REGENITIVE POTENTIAL
AND PROLIFERATIVE POTENTIAL
BECAUSE IT PERPETUALLY
DIFFERENTIATES THROUGHOUT
LIFETIME AND SERVES US WELL.
SO, A SMALL BIOPSY OF HUMAN SKIN
CAN GENERATE ENOUGH PRIMARY
CELLS IN CULTURES TO GENERATE
SHEETS THAT CAN COVER SEVERAL
BASAL FIELDS IN SURFACE AND THAT
IS CURRENTLY BEING USED IN BURN
UNITS WHERE WE ACTUALLY GROW
OTOL GUS CELLS AND APPLY THEM TO
PATIENTS TO ACTUALLY AID IN
THEIR WOUND HEALING.
SO IF YOU THINK ABOUT THE
POTENTIAL, IT'S REALLY
REMARKABLE OF WHAT SKIN AS AN
ORGAN DOES.
IN ADDITION TO THAT, MANY OF YOU
HAVE HEARD HOW THIS WAS A
LANDMARK YEAR OF 2007, WHEN A
SKIN CELL SCIENTIST
INDEPENDENTLY TOOK DIFFERENT
PARTS OF THE WORLD, AND HAVE
COME UP WITH A PROTOCOL WHERE
THEY CAN USE ADULT SKIN CELLS
AND REALLY TURN IT INTO INDUCED
PLURIPOTENT STEM CELLS OR
EMBYRONIC LIVE STEM CELLS AND
NOW BECOME A REALLY POTENTIAL TO
GENERATE DIFFERENT TISSUES.
SO FROM AN ADULT SKIN CELL WITH
FOUR DIFFERENT GENES, SLIGHTLY
DIFFERENT FROM TWO DIFFERENT
COCKTAILS IN TWO DIFFERENT LABS,
BUT AN ADULT SOMATIC SKIN CELL
CAN REALLY BE CHANGED INTO
EMBYRONIC STEM CELL AND THEN
GIVE RISE TO DIFFERENT TISSUES
AND DIFFERENTIATE INTO DIFFERENT
THINGS.
SO IF YOU THINK ABOUT THIS
CONCEPTUAL POTENTIAL OF
REGENITIVE MEDICINE AND TISSUE
REPAIR THAT COMES FROM SKIN, IT
IS REALLY IS REMARKABLE OF HOW
THE WOUND HEALING PROCESS OCCURS
THROUGHOUT THE LIFETIME.
AND IT IS REALLY A COORDINATED
CELLULAR PROCESS THAT AIMS AT
NOTHING ELSE BUT BARRIER
RESTORATION.
WHAT I WAS FATINATED ABOUT IS
YOU CAN TAKE HUMAN SKIN OFF THE
BODY, PUT IT IN THE INCUBATOR,
MAINTAIN IT IN THE EARLY
INTERFACE AND THEN IF YOU WOUND
THAT SKIN, THAT SKIN WILL HEAL.
SO THIS IS RIGHT OUT.
SO THE CELLS DO KNOW HOW TO
CLOSE THE WOUNDS AND HOW TO
ENTER THIS EVOLUTIONARY PROCESS
OF BARRIER RESTORATION.
YOU CONTAIN THIS PROCESS ONE
STEP AWAY AND THEN TAKE THE SKIN
PIECES APART WITH INDIVIDUAL
CELLULAR COMPARTMENTS AND GROW
KERATINOCYTES FIBROBLASTS IN
CULTURE.
THEN RECONSTRUCT 3 DIMENSION
ALLEY THAT TISSUE AND MAKE A
SKIN IN THE PEE TREE DISH.
IF YOU WOUND THAT SKIN, THAT
SKIN WILL HEAL AS THE SLIDES ARE
SHOWING.
SO YOU COULD SEE THIS LEADING
EDGE OF THE EPITHELIUM CRAWLING
OVER THE DERMAL SIDE AND REALLY
CLOSING THE GAP.
SO, THE CELL REALLY DO KNOW WHAT
TO DO ON THEIR OWN WITHOUT ANY
OF OUR HELP.
AND HOW IS THIS PROCESS
ACHIEVED?
THE BASICS ARE CLEARLY IT'S NOT
A SIMPLE PROCESS.
AND THAT IS BOTH EXCITING AND
DIFFICULT WHEN YOU HAVE TO DEAL
WITH TREATMENT DEVELOPMENT
BECAUSE OBVIOUSLY, WHEN YOU HAVE
MULTIPLE CELLS AND MULTIPLE
FACTORS, IT BECOMES A LOT MORE
COMPLICATED STORY.
SO, A WOUND, WHEN A WOUND
HAPPENS, KERATINOCYTES RELEASE
PRESTORED INTERLEUKIN 1 AND THAT
IS IMPORTANT BECAUSE THIS IS
SORT OF A BIG SIGNAL TO THE
SURROUNDING TISSUE THAT THE
BARRIER HAS BEEN BROKEN AND THE
PATHOGENS WERE O. COMING IN.
AND I THINK THAT IF YOU THINK
ABOUT THESE CELLS, THEY ARE
EQUIPPED TO REALLY VERY
PROFOUNDLY ROBUSTLY ALERT THEIR
NEIGHBORS, IF YOU WANT, THAT
BARRIER HAD BEEN BROKEN.
AND IN RESPONSE TO THAT, A LOT
OF THINGS HAPPEN.
KERATINOCYTES START MOVING AND
PROLIFERATING SO OBVIOUSLY TOW
CLOSE THE GAP.
FIBROBLASTS ARE PROLIFERATING
AND LAY DOWN THE MATRIX AND
EPITHELIAL CELLS START SPROUTING
BLOOD VESSELS AND SORT OF THE
FORM OF ANGIOGENESIS,
MACROPHAGES ARE MOVING IN TO
CLEAR UP THE INFECTION.
ALL OF THESE CELLS ARE VERY,
VERY IMPORTANT AND THEY ARE
VERY, VERY WELL COORDINATED IN
TIMELY FASHION IN ORDER TO CLOSE
THIS WOUND.
AND OF COURSE, HOW DOES THAT
HAPPEN?
WELL, THROUGH THE CROSS TALK
AMONG THESE CELLS WITH WONDERFUL
EHILLS AND CELL PHONES AND ALL
THE GADGETS THEY HAVE, GROWTH
FACTORS, AND CHEMOKINES.
THEY TALK TO EACH OTHER AND
SIMULATE EACH OTHER IN A TIMED
RESPONSE IN THE WELL COORDINATED
MANNER.
SO HOW, IF WE DEAL WITH THIS
EXTRAORDINARILY TISSUE THAT CAN
HEAL ON PERPETUAL DOES HE THAT
THROUGH OUR LIFETIME, HOW CAN WE
THEN FACE THIS IN OUR CLINICAL
SIDE?
SO, WE ARE NOW IN THE MIDST OF
EPIDEMIC CHRONIC WOUNDS.
AND SO, WORLDWIDE, THERE IS OR
THERE ARE DATA OUT THERE THAT
SHOW THAT THERE ARE EVERY 30
SECONDS PART OF THE LENSE, LOWER
LENSE, AMPUTATED DUE TO DIABETES
AND I THINK AS THIS DEVELOPS THE
DATA THROUGH 2005 AND AS WE ARE
COMING TOWARDS THIS AGE NOW, I
THINK THE TIME IS SHORTER.
SO, WITH ALL OF THIS ABILITY
THAT WE HAVE AND TECHNOLOGY AND
KNOWLEDGE AND TIME AND
EVERYTHING THAT WE HAVE IN OUR
TOOLBOX, HOW CAN WE USE
AMPUTATION AS A CLINICAL
APPROACH?
THAT IS SIMPLY NOT ACCEPTABLE.
SO, THE FOCUS OF MISLEARNS TO
TRY TO UNDERSTAND WHY WON'T THE
WOUNDINALLY IN A CLINICAL
ARRANGEMENT, WE'RE FACED WITH A
LOT OF PRODUCTS THAT ARE SAFE TO
USE BUT THEY DO NOT REACH THE
THRESHOLD OF CLINICAL EFFICACY.
AND VERY FEW PRODUCTS HAVE
REACHED THAT.
AND THEY ACTUALLY DON'T HAVE ALL
THAT GREAT SUCCESSFUL RATE.
SO CLEARLY WE ARE FACING WITH A
TREMENDOUS CLINICAL BURDEN THAT
REALLY DID NOT COME UP WITH
SOLUTIONS OR TREATMENT
APPROACHES IN THIS BIG FASHION.
SO, WE ARE TRYING TO DO
EVERYTHING AS POSSIBLE WE CAN
FOR OUR PATIENTS BUT I THINK IN
GENERAL, THERE IS A LOT MORE
THAT CAN BE DONE.
SO THE QUESTION REALLY IS, WHY
WON'T WOUND HEAL, AND WHY DO
CELLS WANT THEIR MAGIC TO BE IN
LINE WITH THE TITLE?
SO WE DECIDED TO USE THE
APPROACH AND I TEAMED UP WITH
EXTRAORDINARY TEAM OF CLINICAL
SCIENTISTS AND ONE OF WHICH IS
HAROLD BREAM AND WINTHROP
UNIVERSITY HOSPITAL AND ONE IS
ROBERT AT THE UNIVERSITY OF
MIAMI.
AND YOU KNOW, THESE ARE THE
INCREDIBLE PHYSICIANS WHO TREAT
THESE STATION.
AND HAS BEEN WORKING IN MY LAB
FOR A LONG TIME, FIRST AS A
FELLOW AND NOW AS A JUNIOR
FACULTY, WHO ACTUALLY
PARTICIPATED IN MAJORITY OF THE
STUDIES THAT I WILL SHOW YOU
TODAY.
SO WHAT WE DECIDED TO DO IS
COLLECT THE BIOPSIES IN ONE
STUDY WITH DR. BREN TO COLLECT
THE BIOPSIES FROM WOUND HEALING
EDGE OF THE WOUND AND
STANDARDIZE THESE BIOPSIES AND
DO MICROARRAYS.
AND THE STUDY WITH DR. CECHNER,
WHAT WE HAVE DONE IS WE SELECTED
PATIENTS WHO ARE NONHEALERS AND
HEALING CELLARS AND THEN
COMPARED THE TWO.
WE IMPLEMENTED THIS CLINICAL
OUTCOME IN OUR DESIGN BEFORE WE
DID MY CROW ARRAYS.
SO LI SHOW YOU THE SUMMARY BUT
BEFORE THAT I HAVE TO MAKE A
SLIGHT AXE AGGRESSION TOWARDS
THE STUDENTS THAT I REALLY LOVE
AND FELLOW WHOSE ARE YET TO FACE
THE STUDY SECTION WORLD AND THE
GRANT APPLICATION WORLD.
AND IT IS FROM GRANT THAT
ACTUALLY, NATIONAL INSTITUTE OF
NURSING RESEARCH FUNDED BUT
THERE WAS BEFORE THE ONE
SUBMISSION BEFORE THE ONE THAT
GOT FUNDED.
AND BASICALLY WHAT I PROPOSED TO
DO GLOBAL TRANSCRIPTIONAL
ANALYSIS OF WOUND HEALING, ONE
REVIEWER SAID IT'S SIMPLY NOT
POSSIBLE.
SO, THIS IS REALLY VERY
IMPORTANT SORT OF DENSE AND YOU
WILL RECEIVE A LOT OF REVIEWS IN
YOUR LIFE FROM GRANTS AND
PAPERS.
AND EVERY SINGLE ONE OF THEM
DOES INFLUENCE IF YOU MANY WAYS.
SO ONCE YOU SET THAT ASIDE AND
LOOK INTO THE MESSAGE, TO ME THE
MESSAGE WAS REALLY CLEAR.
HE SAID, YOU KNOW WHAT?
I BELIEVE IT WHEN I SEE IT.
AND SO, WHAT I AM EXCIDE SAID TO
REAL DOE THIS AND RESEARCH THE
GRANT AFTER I DONE THE INITIAL
STUDIES AND THE GRANT GOT FUNDED
AND HERE I AM.
BECAUSE EVERYTHING I HAVE TO SAY
STARTED WITH THIS ORIGINAL GRANT
AND THE ORIGINAL STUDY.
SO BEFORE THE MICROARRAYS ARE
BEAUTIFUL YOU SHOW THEM AND
ESSENTIALLY THE LEFT THREE
PATTERNS ARE GENE PATTERNS AND
HEAT MAPS OF NONHEALING EDGES OF
THE VENUS ULCERS.
WE COMPARED THIS TO AN
IDENTIFIABLE PATTERN OF GENES
THAT REALLY SHOW AND RESEMBLE
NONHEAVYING.
WHEN YOU ZOOM IN, YOU UNDERSTAND
THERE IS ABOUT 1500 OF THEM THAT
ARE STATISTICALLY SIGNIFICANT,
DEREGULATED IN THE CHRONIC
NON-HEALING WOUND EDGE.
AND OF COURSE, I WILL NOT GO
INTO DOE TAILS BUT MANY OF THEM
RELATE TO THREE IMPORTANT
KERATINOCYTE PROFILES.
SWONE CARE 10O SITE
DIFFERENTIATION, ONE IS
MIGRATION ABILITY AND
PROLIFERATION.
AND I WILL TODAY TALK ABOUT
PROLIFERATION AND MIGRATION
PRIMARILY.
BUT WHEN YOU SORT OF -- WHEN YOU
LOOK AT THAT PROFILE, AND THEN
YOU GO BACK AND LOOK AT THE
PATIENT SAMPLES AND HISTOLOGY,
YOU WHAT ACTUALLY SEE IS THAT
EVERYTHING WE SAW IN THE
MICROARRAYS IS REALLY TRUE.
FIRST YOU ACTUALLY FIND
TREMENDOUSLY HYPERPOLICE
OFFICERRENCE IN EPIDERMIS.
WHEN YOU ZOOM IN, YOU COULD
ACTUALLY APPRECIATE THERE ARE
DIVISIONS SUPER BASALLY,
DIFFERENTIATED AS IF THE DERMIS
NEVER HAPPENS.
IF YOU LOOK AT THIS QUANTIFIED
LAYER, WHICH IS SUPPOSED TO BE
WITHOUT NUCLEI AND THAT CELL
LAYER THAT REALLY NEEDS TO
PROTECT US, YOU APPRECIATE THAT
THERE IS A LOT OF NUCLEI THERE.
SO, WHAT THIS MEANS IS THAT THE
CELLS REALLY DO NOT EXECUTE
PROPERLY THE DIFFERENTIATION
PROCESS.
BUT THEY ALSO DON'T COMPLETELY
EXECUTE THIS ACTIVATION PROCESS
OF WOUND HEALING WHERE THEY ARE
PROLIFERATING BUT THEY KIND
OF -- THEY CANNOT MOVE SO THERE
IS AN INHIBITION OF MIGRATION
AND LOSS OF DIFFERENTIATION IF
YOU WILL AT THIS NONHEALING
EDGE.
SO, THERE IS THIS RISK THAT
HAPPENS AND ALMOST LIKE A GRAND
CANYON.
A BIG PILE OF CELLS THAT ARE
DISORIENTED IN SPACE AND TIME
AND THEY CANNOT DO ANYTHING WHAT
THEY ARE SO WELL PROGRAMSED TO
DO.
THAT PROSFASCINATES ME AND WE
REALLY TRIED EXPLAIN WHY.
SO AS I SAID, ONE OF THE
CHARACTERISTICS OF KERATINOCYTES
IS HYPERPROLIFERATION.
THE FIRST QUESTION WE WANTED TO
ASK IS WHAT IS THE FATE OF
PROGENITOR CELLS IN CHRONIC
BOUNDS WE START TO LOOK AT THE
EPIDERMAL STEM CELLS.
LI NO GOT INTO DETAILS OF THE
BEST PARTS OF BIOLOGY BUT
IMPORTANT TO KNOW OBVIOUSLY IF
ANY STEM CELLS ARE KEPT IN
MOSTLY QUIESCENT TIMES BUT
WHETHER A CYCLING NEEDS TO
HAPPEN, THEN THERE ARE A COUPLE
OF EVENTS AND SIGNALING
MOLECULES THAT NEED PLAY A ROLE.
ONE IS THE BMPR1 ALPHA NEEDS TO
BE DOWN REGULATED.
DATA 3 NEEDS TO BE DOWN
REGULATED AND BAIT CATEEN IN
NEEDS TO BE INDUCED IN ORDER FOR
STEM CELLS TO GO FROM QUIESCENCE
TO CYCLING.
WHAT WE WANTED TO REALLY LOOK
INTO IS WHAT HAPPENS WITH ALL OF
THESE REGULATORY MOLECULES IN
THE CONTEXT OF THE CHRONIC WOUND
PATIENT?
AND THEN WHAT WE FOUND OUT IS IF
YOU LOOK AT THE LEFT SIDE OF
THESE TWO IMPORTANT MOLECULES
THAT ARE REAL -- THEY ARE DOWN
REGULATED, THEY ARE DOWN
REGULATED IN ULCER AND, AND THEY
NEED TO BE DOWN REGULATED IF THE
STEM CELL IS ENTERING THE
CYCLING MODE AND LEAVING THE
QUIESCENT MODE.
SO THIS KIND OF PROPS THAT MAY
BE IS THERE A SPECIALIST
QUIESCENT TO CYCLING IN THE
CONTEXT OF THE CHRONIC WOUND
ENVIRONMENT.
AND THEN WHEN YOU LOOK AT THE
SECOND PART OF THE EQUATION,
WHETHER THERE IS ACTIVATION OF
BETA CATENIN, WE FOUND A
PROFOUND INDUCTION OF NUCLEAR
BAIT CATEEN IN IN THE NONHEALING
WOUND AND A CONSEQUENCE OF
STIMMIC, WHICH LEADS TO
HYPERPROLIFERATION OF THE
EPIDERMIS.
AND WHAT IS INTERESTING ABOUT IT
IS THAT LONG BEFORE WE STARTED
LOOKING AT THIS, WE HAVE SHOWN
THAT IF YOU OVEREXPRESS C MYC IN
EPIDERMIS OF MOUSE SKIN.
THESE MOUSE WILL SPONTANEOUSLY
DEVELOP CHRONIC WOUNDS.
SO CLEARLY THIS PATHWAY DOES
PLAY A ROLE IN THE CONTEXT OF IT
AND THEN SO MANY YEARS LATER
WHEN WE START LOOKING AT
PATIENTS, WE KIND OF GET INTO
THE SAME STORY.
AND WHICH IS ALWAYS NICE TO GET
A CONFIRMATION OF THIS.
SO WE HAVE A HYPERPROLIFERATIVE
EPIDERMIS.
NOW, AS A SIDE PART OF THAT, SO
YOU HAVE A HYPERPROLIFERATIVE
EPIDERMIS BUT THEN OKAY, WHAT
WAS STRIKING TO US IS THE FACT
THAT THERE IS ACTUALLY A
COMPLETE LOSS OF EPIDERMAL STEM
CELLS IN THIS HYPERPROLIFERATIVE
EPIDERMIS.
ONE OF THE MARKERS IS K15,
KERATIN 15.
AND THIS IS THE NORMAL SKIN AND
YOU CAN APPRECIATE THE BASAL
LAYER STAINING THAT IS
COMPLETELY GONE IN A NONHEALING
EDGE OF THE CHRONIC WOUND.
SO THIS FREQUENT CYCLING MIGHT
LEAD TO THE DEPRIVATION OF THE
SOURCE OF THE STEM CELLS IN THE
ENVIRONMENT OF A NON-HEALING
WOUND.
THANKFULLY ALL WENT ON AND
BECAME TRANSIENT TO FIND CELLS.
YET THE WOUND DOESN'T HEAL AND
IT'S NOT HEALED BECAUSE THERE IS
NO MIGRATION.
SO THESE CELLS ARE PILING BUT
THEY ARE NOT MOVING AND THIS
OBVIOUSLY HAPPENS BECAUSE OF ALL
OF THESE SIGNALS THAT ARE REALLY
NOT COMING.
SO NOT ONLY ARE THEY NOT
MIGRATING IN LOCAL BUT THEY
VALUES A LOSS OF HOMING AND LOSS
OF DIFFERENT CHEMOKINES AND
CYTOICANCY WHERE THEY CANNOT
CALL THE PROGENITORS WHO COME TO
THE SITE OF THE WOUND.
SO IN ADDITION TO NOT BEING ABLE
TO MIGRATE, THEY ALSO CANNOT
CALL THE CELLS, OTHER CELLS SUCH
AS CIRCULATING PROGENITORS, BONE
MARROW PROGENITORS, EPITHELIAL
PROJEN TORS OR LOCAL EPIDERMAL
STEM CELLS TO COME AND AID IN
WOUND HEALING.
SO NONE OF THAT HAPPENS.
WHEN WE START LOOKING INTO
SIGNALING THAT CONTROL MIGRATION
AND THIS WHOLE PROCESS, WE
ACTUALLY LOOKED AT FOR EXAMPLE,
THE EGF RECEPTOR AND WE FOUND
REALLY THAT INTERESTINGLY, THERE
IS ALMOST A SLIGHT
DECREASE - AUTO PROFOUND
DECREASE OF EPIDERMAL GROWTH
FACTOR RECEPTOR IN THE
NON-HEALING WOUND.
WHAT IS INTERESTING ABOUT IT IS
THAT THAT A LITTLE BIT OF -- I'M
NOT SURE WHETHER YOU CAN SEE,
IT'S CYTOPLASMIC.
SO IF YOU THINK ABOUT WHAT EGF
RECEPTOR NORMALLY DOES, IT SITS
ON THE MEMBRANE AND RECEIVES A
SIGNAL.
HERE IN THE NONHEALING WOUND,
YOU REALLY DON'T HAVE THAT
RECEPTOR IN THE MEMBRANE WHERE
IT SHOULD BE.
SO, IF YOU APPLY EGF RECEPTOR
EXTERNALLY TO THE PATIENT, THERE
ARE NO CELL THAT IS CAN RESPOND
TO IT.
SO THE CLINICAL TRIAL OF TESTING
EGF RECEPTOR WOULD NOT MAKE ANY
SENSE BECAUSE THERE IS SIMPLY NO
WAY OF REALLY TRANSMITTING THAT
SIGNAL EVEN IF IT'S EXTERNALLY
APPLIED.
AND I THINK THAT IS ONE ASPECT
THAT IS VERY IMPORTANT TO
UNDERSTAND.
THE TRANSITION FOR PRECLINICAL
TESTING TO HUMAN SITUATION AND
CLINICAL TESTING, REALLY CALLS
FOR LOOKING INTO PATIENT SAMPLES
MUCH MORE CAREFULLY TO MAKE SURE
THAT THEY WILL BE ABLE TO
RESPOND TO WHATEVER WE ARE
OFFERING TO THEM.
THE SAME THING, AND I WILL NOT
GO INTO DETAILS, THE TAKE HOME
MESSAGE OF THIS COMPLICATED
SLIDE, THAT A NONHEALING EDGE OF
A CHRONIC ULCER, WE GET THE
SAMIZATION NONE OF THE RECEPTORS
ARE ON THE MEMBRANE BUT THEY ARE
SIGNALING MOLECULES ARE NOT IN
PLACE THEY ARE IMPAIRED IN THEIR
FUNCTION.
SO, AT THE END OF THE DAY, WHEN
YOU LOOK AT THIS, WE DID A
MICROARRAY STUDY WHERE WE
COMPARED, THIS IS MICKEY
BLOOMBERG WHO COLLABORATED WITH
US AND THE LEAD EDITOR ON THIS
PAPER.
WHAT HAPPENED HERE IS THAT GENES
THAT TGF BETA NORMALLY REGULATES
IN HEALTHY SKIN OR HEALTHY
WOUNDS, ACTUALLY ARE REGULATED
IN A NON-HEALING OF THE CHRONIC
ULCER SIMPLY BECAUSE THERE IS NO
WAY OF PROPER SIGNALING OF THE
TGF BETA IN THE CONTEXT OF A
NON-HEALING EDGE.
SO ANOTHER THING, SO WE ARE
STILL SEARCHING OF WHY THIS
SIGNALING IN PARIS AND HOW THE
GROWTH FACTORS AND ALL OF THAT
REALLY INFLUENCES MIGRATION.
AND WHEN YOU DO MICROARRAYS, WE
ALL KIND OF HAVE A SET OF OUR
CHOICES THAT WE ARE EXPECTING TO
SEE AND ARE VERY EXCITED TO SEE
THAT IT WILL CONFIRM, BUT THEN
WHAT WE ESSENTIALLY DO IT FOR
THE SURPRISE IS AND I THINK THAT
IS THE BIG PART OF GENOMICS
APPROACH IS WHERE YOU REALLY
DON'T KNOW WHAT YOU'RE GOING TO
FIND.
AND ONE CANDIDATE THAT WE REAL
DID HE NOT EXPECT WAS ADAM 12 TO
FIND IN A NONHEALING EDGE.
AND THIS IS A MOLECULE THAT
REALLY IS VERY INTERESTING AND
IT HAS A LOT OF PARTS AND
FUNCTIONS AND A LOT OF THINGS
BUT IT'S ACTUALLY DIFFERENT
GRIN.
SO IT ALSO REGULATES THE
INTERGRINS AND REGULATES A LOT
OF SIGNALING.
SO, WHEN WE STARTED LOOKING, WE
HAVE BEEN A LOT SURPRISED, NOT
ONLY THEY IT IS UNIQUELY INDUCED
IN CHRONIC WOUNDS BUT ALSO THAT
IT'S NOT REGULATED IN ACUTE
WOUND HEALING PROCESS OF HUMAN
SKIN.
SO IT BECOMES ONLY PRESENT AND
INDUCED NORMALLY DOESN'T
FUNCTION AND DOESN'T DO A LOT
DURING THE REGULAR WOUND HEALING
BUT IN A CHRONIC WOUND, IT GETS
TURNED ON TREMENDOUSLY AND YOU
CAN APPRECIATE THAT HERE ON THE
PROTEIN LEVEL EVERY PANEL OF
THESE ROUND ONES IS A DIFFERENT
ULCER AND DIFFERENT PATIENTS.
SO YOU CAN APPRECIATE THIS.
I HAVE TO SAY IT'S A BEARER OF
BAD NEWS IN GENERAL AND IF YOU
LOOK AT THE BLADDER CANCER FOR
EXAMPLE, YOU COULD FIND A. ADAM
12 SECRETED IN URINE OF A
PATIENT WHOSE TUMOR IS GOING TO
GO.
SO IN A WAY, IT KIND OF ALERTS
TO THE BAD SITUATIONS AND
CLINICAL OUTCOMES WE STILL DON'T
KNOW EXACTLY HOW AND WHY IN THE
CONTEXT OF A CHRONIC WOUND.
AND STUDY WAS DONE WITH CARL
FROM CORNEL AND HSS.
SO WHAT WE HAVE DONE IS
GENERATED A TRANSGENIC MOUSE
WITH ADAM 12 WHERE WE ACTUALLY
KNOW HOW ADAM 12 AND OBVIOUSLY
WHEN YOU THINK ABOUT IT, SO IF A
LOT OF ADAM 12 INHIBITS HEALING
AND KNOCK IT OUT, YOU EXPECT THE
CELLS WILL MIKE RATE AND THAT'S
WHAT WE GET.
AND THIS IS MORE VISUAL WAY OF
TESTING THE MIGRATION ON ITS OWN
WHEN YOU ACTUALLY TAKE THE
BIOPSY OFF OF IN AND YOU PUT AND
MEASURE THE OUTPUT.
SO IT'S AN INVERSE VERSION OF
WOUND HEALING WHERE YOU ARE
EXPECTING TO CLOSE YOU'RE NOW
MEASURING THE CELLS AND HOW FAR
AND HOW WIDE THEY CAN ACTUALLY
MIGRATE.
SO AND THE STAINING HERE IS
SHOWING THAT THESE ARE ACTUALLY
KERATINOCYTES BECAUSE THIS IS
SPECIFIC ANTIBODY.
SO IN ADDITION TO WHAT WE
ALREADY KNEW ABOUT CHRONIC
WOUNDS THAT HAVE INCREASED PRO
TAZE ACTIVITY, WE FOUND INCREASE
OF ADAM 12 AND THAT MAY BE
LEADING TO INCREASED PROCESSING
AND GROWTH FACTORS AND CHANGE
INTERACTIONS WITH EXTRACELLULAR
MATRIX AND SIGNALING ALL OF
WHICH WOULD POSSIBLY LEAD TO
INHIBITION OF WOUND HEALING.
SO THE OBVIOUS QUESTION IS SO
WHAT REGULATES ALL OF THIS WHAT
I TOLD YOU?
IT'S WHAT ARE THE REGULATORS AND
WHAT ARE THE MAIN SWITCHERS?
SO WE START LOOKING INTO
MICROARRAY.
MARK ROW RNAS AND I WILL NOT
REALLY GO INTO DETAILS WHAT HAVE
THEY DO BUT FOR THE TAKE HOME
MESSAGE, THE IMPORTANT THING IS
WHEN YOU HAVE A MESSAGE
OBVIOUSLY IN THE PROTEIN, WHEN
YOU HAVE A MICRORNA PRESENT,
THAT DOESN'T HAPPEN.
SO ESPECIALLY YOU CAN HAVE A
FULL TRANSCRIPTIONAL REGULATION
AND YOU DO HAVE EXPRESSION OF
THE MESSAGE BEING MADE BUT THEN
MIRNA COMES IT NEVER ATHROUGHS
TO TURN INTO PROTEIN.
AND SO, WE THOUGHT THAT MAYBE IF
WE APPROACH THIS GENOMICS
PROFILE THAT WE HAVE FROM OUR
PATIENTS, AND IF WE USE THE
REVERSE GENOMICS WITH THE HELP
OF CHRISTINA FROM
SLOAN-KETTERING WHO IS IN
COMPUTATIONAL BIOLOGY, BUT IF
YOU TAKE THESE GENES, THESE 1500
REGULATED GENES AND JUST SAY,
OKAY, IF MICRORNAs ARE TARGET
GENES WHICH MICRORNAs WOULD BE
REGULATED IN THAT TISSUE IF
THESE ARE THEIR TARGETS AND
THAT'S HOW THEY ARE EXCESSED.
SO THAT IS SORT OF REVERSED
COMPUTATIONAL ANALYSIS LEAD TO A
LIST OF MICRORNAs THAT MIGHT
BE REGULATED IN THE CHRONIC
WOUND AND SO, AGAIN, THOSE WHO
WE COLLABORATED WITH IN THIS
STUDY IN MIAMI, WE START LOOKING
IN THE DIFFERENT LEVELS AND WE
FOUND THEY ARE ALL INITUDES AND
YOU THIS IS ONE OF THEM, THIS IS
THE MICRORNA21 ASK, AND THIS IS
THE BIOPSY AND YOU CAN
APPRECIATE THIS IS IN SITU
HYBRIDIZATION SHOWING
MICRORNA21.
SO I WILL NOT GO INTO DETAILS.
THERE ARE A LOT OF DATA THERE.
BUT IN ORDER TO SHIFT TO THE
PATIENCE AND TALK ABOUT
TRANSLATIONAL ASPECTS, I WILL
NOT SPEND A LOT OF TIME ON THIS
SUBJECT.
BUT DID IS IMPORTANT THAT WE
HAVE IDENTIFIED AND DOCUMENTED
AND PROVED THAT THESE
MICRORNAs THAT WE FOUND
INDUCED IN PATIENTS WITH CHRONIC
WOUNDS TARGET SIGNALING
MOLECULES THEY DO REGULATE THEIR
EXPRESSION.
OR THEIR PROTEIN LEVELS IF YOU
WANT.
AND THAT IS ONE OF THE PROFOUND
AND IMPORTANT ISSUES WITH A
CHRONIC WOUND AND SOMETHING THAT
WE REALLY CLINICALLY NEED TO
KNOW.
SO ESSENTIALLY, IF YOU LOOK AT
THE DIABETIC FOOD ULCER, FOR
EXAMPLE, WHAT HAPPENS TO THESE
CELLS, UNLIKE IN ACUTE WOUND
WHEN THESE CELLS START
MIGRATING, THAT DOESN'T HAPPEN.
THEN THE FIBROBLAST REALLY STOP
PROLIFERATING AND THEY DO NOT
LAY PROPERLY, THE MATRIX AND
EPITHELIAL CELLS ARE NOT
MIGRATING AND DECREASE OF
ANGIOGENESIS.
MACROPHAGES DON'T COME IN THE
SITE OF THE WOUND IN THE NUMBER
OF READY TO FIGHT INFECTION AND
YOU HAVE IN ADDITION ALL OF
THIS, IS FORMATION OF
COLINNIZATION AND UNFORTUNATELY
MICROBIAL BIOHELD AND THIS WOUND
TURNS IN CHRONIC AND INFECTED
AND IS THERE A REALLY BAD
OUTCOME FE AT THE END FOR YOUR
PATIENTS.
SO HOW IS THIS ACHIEVED?
THE DECREASE IN GROWTH FACTOR
COO CYTOKINES AND CHEMOKINES IS
ONE OF THE REASONS WHY NONE OF
THIS REALLY HAPPENS.
AND SO, TURNING FROM HEALING TO
CHRONIC WOUND AND TRYING TO WRAP
UP WITH WHAT I HAVE SAID SO FAR,
IS THAT THERE IS INCREASE OF
MICRORNA MOLECULES IN THE
NONHEALING WOUND AND THAT READS
TO DEREGULATION OF THE SIGNALING
MOLECULES THAT, AS AN OUTCOME ON
THE CELLULAR PROCESS HAS
MIGRATION AND HYPERPROLIFERATION
AND LOSS OF LOCAL AND EVER STEM
CELL CYCLING AND THEIR LOSS IN
THE AREA OF THE NONHEALING WOUND
AND THEN OBVIOUSLY LOSS OF
DIFFERENTIATION.
ALL OF THIS REALLY INHIBITS
WOUND CLOSURE AND EPITHELIAL
EVASION.
AND WOUND IS NOT HEALED UNLESS
IT IS CLOSED.
AND THAT MEANS UNTIL
KERATINOCYTES DO THEIR JOB, THE
WOUND IS NOT CLOSED.
AND THEREFORE THERE IS NO
HEALING.
AND KEEP IN MIND OBVIOUSLY THAT
I HAVEN'T TALKED ABOUT OTHER
COMPONENTS.
SO WE ARE JUST AN EPIDERMIS.
THIS IS ONE ASPECT OF THE WHOLE
PROCESS AND I COULD NOT LIST ALL
THE PARTICIPANTS BUT YOU KNOW,
WE DIDN'T DISCUSS TODAY
GRANALATION TISSUE FORMATION IN
THE CONTEXT OF CHRONIC WOUNDS,
NOR ANGIOGENESIS OR THIS CROSS
TALK OF THE MICROBIOFILM AND
CHRONIC WOUND.
SO CLEARLY THERE IS -- WE HAVE
OUR SCIENCE WORLDCOM COMPLETELY
CUT OUT FOR US.
NOW THE BIGGEST QUESTION THAT
MANY LABS PACKING THIS AND
TRYING TO UNDERSTAND IT IS WHY?
AND WHAT IS UPSTREAM OF ALL OF
THIS?
WHAT REGULATES THIS MICRORNA AND
NOT ONLY MICRORNAs?
THERE ARE NO MAGIC MOLECULES.
I DON'T WANT YOU TO GO HOME AND
THINK IT'S EASY.
WE CAN JUST REVERSE NIECE WE ARE
DONE.
THAT'S NOT GOING TO HAPPEN,
RIGHT?
SO I THINK THAT UNDERSTANDING
WHAT COMES UPSTREAM OF ALL OF
THIS THAT I HAVE TOLD YOU WILL
BE REALLY IMPORTANT AND THAT IS
WHERE THE EXCITEMENT RIGHT NOW
IS AND THERE ARE A LOT OF WORK
BEING DONE ON THAT.
AND ESSENTIALLY AND CONCEPTUAL
FRETHIS HEALING TO A NONHEALING.
RIGHT?
SO YOU CAN REALLY THINK ABOUT IT
IN TWO WAYS.
SO EITHER THE CELL TRANSITIONED
AND CROSSED OVER TO THE WORLD
AND IT CANNOT GO BACK, SO THIS
IS SORT OF TERMINAL, IT'S
NONHEALING AND THERE IS NO WAY
BACK.
SORE THIS CELL HAS TO UNDERGO
AND UNDERWENT REALLY A BAD SET
OF DECISIONS AND SIGNALS AND
THEN GOD KNOW WHAT IS ELSE AND
END UP NONHEALING BUT IS THERE A
HOPE AND SWITCHES CAN BE
REVERSED AND THEY CAN REALLY BE
TRANSITIONED OVER.
AND ACTUALLY, BOTH OF THESE ARE
CLINICALLY VALID APPROACHES AND
THEN SO WHEN I TALK ABOUT THE
FIRST PART AT CLINICAL MEETINGS,
THEY ALL SHRUG SHOULDERS AND SAY
WHAT CAN WE DO TODAY FOR OUR
PATIENTS?
SO, THE CURRENT APPROACHES ARE
TWO.
OBVIOUSLY ONE IS REMOVE THE
NONHEALING CELLS AND THE OTHER
APPROACH IS REVERSE.
IT'S VERY SIMPLE IF YOU THINK
ABOUT IT.
SO EITHER YOU CAN JUST CUT THEM
OUT AND KEEP THOSE THAT ARE
ACTUALLY DO HAVE HEALING
PHENOTYPES OR YOU CAN TRY TO
REALLY CONVERT THEM.
THIS MIGHT BE MAYBE MORE
DIFFICULT BUT THEN MAYBE MORE
PERMANENT SOLUTION.
AND SO BOTH OF THEM ARE
CLINICALLY VAL IN THE CLINIC.
BUT IT'S NOT THAT EASY WHEN YOU
HAVE REMOVED NON-HEALING CELLS
CELLS.
SO WHAT DOES THAT MEAN?
HOW DO YOU KNOW WHICH ONE IS
REALLY NONHEALING CELL AND THE
TISSUE PART AND HOW YOU'RE GOING
TO CUT IT OUT IF YOU DON'T KNOW?
SO, WE CLEARLY NEED SOMETHING
MORE OF THE SOPHISTICATED
APPROACH TO CREATE THIS
MOLECULAR -- WE CAN KNOW AND
GUIDE THE EXTENT OF SURGICAL
DEBRIEFMENT IN THE CHRONIC
BOUNDARY MOVING THIS TISSUE.
SO IF YOU LOOK AT THE CONCEPT OF
MOST SURGERY IN SKIN TUMOR
CELLS, WHAT HAPPENS IS WHEN A
TUMOR IS IN THE SKIN OF MOST
SURJOHNSES AND CUT OUT A TUMOR
AND THEN THEY ANALYZE IT UNDER
THE MICROSCOPE WHILE THE PATIENT
STILL ON THE TABLE.
THEY LOOK TO SEE HISTOLOGY
WHETHER THEY ARE EFFICIENT IN
REMOVING THE BAD TISSUE.
SO IS IT ALL TUMOR TISSUE GONE?
AND IF IT'S NOT, THEY GO BACK
AND THEN REPACK AND THEN UNTIL
IT IS CLEAR AND HISTOLOGY SHOWS
THE NORMAL SKIN TISSUE, THIS
PATIENT IS STILL IN THE ROOM AND
IS BEING TREATED AND DEBREEDED.
IF WE BORROW THAT APPROACH, AND
WE USE THAT STRATEGY TO REALLY
TRY TO DEBRIEF CHRONIC WOUNDS,
WE CLEARLY NEED MORE THAN A
MICROSCOPE AND HISTOLOGY.
THEN WE CAN ANALYZE THIS TISSUE
AND TRY TO COME UP WITH SHOULD
GO THAT WILL TELL US HOW FAR TO
GO.
AND THEREFORE DEVELOPMENT OF THE
BIOMARKERS AND ANY POSSIBLE WAY
IMAGINABLE.
LI SHOW YOU THE APPROACHES WHERE
WE ARE AT THIS STAGE.
BUT THE BOTTOM LINE IS, SO IF
YOU CAN TELL WHAT IS THE
NONHEALING TISSUE, EVEN THOUGH
IT MIGHT NOT HAPPEN BECAUSE WE
STILL DON'T HAVE A REALLY QUICK
MASSIVE TO-DO LIST, BUT IF YOU
ACTUALLY KNOW THAT YOU HAVE THE
ABILITY OF PATIENTS FAR ENOUGH
THEN YOU MIGHT GO AND REDO THAT
MORE EFFICIENTLY AS QUICKLY AS
YOU CAN TO GET THAT PATIENT
GOING.
AND SO, IS THERE ANY BIOLOGICAL
BASIS TO WHAT I AM TELLING YOU?
THE OTHER IMPORTANT QUESTION IN
THE CLINICAL ARENA OF WOUND
HEALING IS, CAN WE TELL WHEN A
PATIENT COMES IN ON THAT FIRST
VISIT WHETHER IF WE ARAPPLY
STANDARDS OF CARE, THIS PATIENT
WILL GO ON TO HEAL OR DO WE
HAVE -- OR WILL NOT.
SO THE QUESTION PREDICTED
BIOMARKERS WHETHER WE CAN
PREDICT CLINICAL OUTCOMES EARLY
ON, WILL CLEARLY DEFINED HOW WE
ARE GOING TO TREAT THE PATIENT.
BECAUSE I HAVE TO SPEND MORE
TIME EXPLAINING TO YOU WHY IT'S
IMPORTANT TODAY.
YOU WHAT DO IS YOU APPLY
STANDARDS OF TREATMENT PROTOCOL
FOR FOUR WEEKS AND THEN YOU
MEASURE THE SIZE OF THE WOUND IN
EVERY VISIT AND DRESSING AND
YOU'RE LOOKING WHETHER THAT
WOUND HAS HEALING TRAJECTORY.
AND IF IT HEALS LATER THAN 50%
THAT PATIENT WILL HEAL WITH THE
STANDARDS OF CARE.
BUT IF IT, BY WEAK FOUR, THIS
DOES NOT HAPPEN, THEN BIOLOGICAL
APPLICATIONS -- THEN DIFFERENT
TREATMENT PRO PROTOCOL GETS
IMPLEMENTED AND MORE BIOLOGICAL
TREATMENTS ARE BEING OFFERED TO
THE PATIENT IN ORDER FOR THEM TO
HEAL.
SO, AND THIS IS BASICALLY BASED
ON WORK FROM DAVID WHO HAS SHOWN
THIS FOUR WEEK OUTCOME IS A
SURROGATE ENDPOINT AND REALLY
IMPORTANT TO REALLY KNOW THAT.
SO IF WE DON'T HAVE TO WAIT FOR
FOUR WEEKS, UNTIL WE ACTUALLY
HELP THE PATIENT WHO IS NOT
HEALING, IF T. WILL BE
TREMENDOUS CLINICALLY IF WE CAN
TELL THAT FROM THE FIRST VISIT
AND REALLY START VERY AGGRESSIVE
TREATMENT PLANS FROM THE GET GO.
AND OF COURSE, A VERY DECISIVE
BIOLOGICAL TREATMENT ON PATIENT
WHO DON'T NEED IT.
SO THERE ARE TWO DIFFERENT
BENEFITS OF THIS APPROACH.
AND SO, WHAT WE HAVE SET UP TO
DO IS WE DECIDED TO COLLECT
SPECIMENS BEFORE AND AFTER
SURGICAL DEBRIEFMENT AND REALLY
RIN ALL THE POSSIBLE ANALYSIS.
SO IN ADDITION, WE HAVE GROWN
PRIMARY CELLS OUT OF THESE
WOUNDS AND STUDIED THEM IN
CULTURE AND ALSO LOOK AT
DIFFERENT VORACITY OFINALIS AND
HISTOLOGY AND
IMMUNOHISTOCHEMISTRY.
ONE THING HAD BECOMES APPARENT.
ON THIS NONHEALING EDGE OF WOUND
HEALING, I TOLD YOU WHAT HAPPENS
IN EPIDERMIS.
BUT THERE THIS SAY DERMAL SITE
AND YOU CAN SEE THERE IS A
PROFOUND LEVEL OF FIBROSIS US
THAT RESOLVES PARTIALLY IN THIS
POSITIVE REASON AND BIOPSY AND
THIS IS HOW NORMAL SKIN LOOKS
LIKE.
BUT ONE THING WAS STRIKING
BECAUSE GRANALATION TISSUE IS
ALWAYS A BIG PROBLEM IN THE
CHRONIC WOUNDS AND I ALWAYS
THOUGHT THAT THERE IS NOT ENOUGH
COLLAGEN.
BUT WHEN YOU LOOK AT THE
COLLAGEN STAINING, SOCIETY CELL
MAKES THE COLLAGEN ANALYSIS AND
LAYS IT OUT AS A MATRIX.
SO IF YOU LOOK AT, IT IT WILL BE
MADE IN CELL AND COULD
APPRECIATE THERE IS A LOT MORE
CELL MAKING COLLAGEN A
NONHEALING WOUND THAN THE
POSITIVE BIOPSY.
BUT YET WHEN YOU LOOK AT THE
COLLAGEN ORIENTATION LOOK AT THE
POLARIZED RIGHT AND HOW THIS
COLLAGEN MATRIX IS LAID OUT,
THEN YOU CAN APPRECIATE IT
REALLY THIS IN A NONHEALING
EDGE, THIS REALLY DOES NOT --
THIS OBVIOUSLY CONTRIBUTES TO
THE LACK OF MIGRATION IN THE
EPITHELIUM.
AND AGAIN, POSITIVE BIOPSY LOOKS
A LOT BETTER.
AND THIS IS HOW THE NORMAL SKIN
LOOKS LIKE.
SO, OBVIOUSLY, STRIKING
DIFFERENCES THAT YOU WOULD
EXPECT IN GENE PROFILES, SO
AGAIN THIS IS A NONHEALING
PROFILE AND TREMENDOUSLY
DIFFERENT IN POSITIVE BIOPSY.
AND SO IF YOU THINK ABOUT THESE
ARE ALL THE CELLS AS A PART OF
THAT WOUND, AND SO THERE IS
CLEARLY A SET OF CELLS THAT HAVE
NOT ONLY DIFFERENT PROFILES OF
DIFFERENT HEALING POTENTIAL,
WITHIN THAT WOUND AND BEING ABLE
TO REALLY REACH OUT TO THEM AND
FIND THEM AND SIMULATE THEM TO
REALLY COME AND DO WHAT THEY ARE
SO WELL-KNOWN TO DO, WOULD BE
REALLY TREMENDOUS.
AND IF YOU THINK ABOUT THIS,
IT'S ANOTHER ASPECT OF IT.
WE CAN ACTUALLY USE THE GENE
PROFILE TO TELL US WHETHER WE
ARE FAR ENOUGH AND I WILL SHOW
YOU A LITTLE BIT LATER OF HOW WE
CAN ACHIEVE THAT.
NOW WHEN YOU LOOK AT THE PRIMARY
CELL GROUND FROM THE WOUND THAT
A NONHEALING EDGE, YOU CAN
AGAIN, I'M NOT SURE HOW FAR YOU
CAN APPRECIATE RESOLUTION BUT
THESE CELLS ARE REALLY THEY LOOK
SICK, NOT NORMAL, THEY ARE BIG
AND LARGE AND DON'T MOVE AT ALL.
WHEN YOU LOOK AT THE CELLS FROM
POSITIVE BIOPSY, CLEARLY THEY
WILL COME UP LIGHT TO NORMAL
CELLS.
WHEN YOU TRY TO TEST THEIR
MIGRATION CELLS, I HAVE TO SAY
THAT I WAS A BIG POLICE OFFICER
WHEN YOU GROW PRIMARY CELLS OUT
OF NONHUMAN WOUND AND PUT ALL
THE CYTOKINE OF THE GROWTH MEDIA
THAT THESE CELLS WILL REVERSE ON
THEM AND THERE WILL BE NO
DIFFERENCE WHEN YOU GROW THEM
LONG IN CULTURE.
BUT INTERESTINGLY ENOUGH, NOT
ONLY DON'T GROW WELL BUT THEY
ALSO DO NOT MIGRATE AND DON'T
RESPOND TO GROWTH FACTOR SIGNALS
AT ALL.
FROM THE NONHEALING EDGE.
THE POSITIVE BRIEFMENT BIOPSY IS
A DIFFERENT STORY.
THESE CELLS ARE ABLE TO MIGRATE
AND AS I SAID, THOSE OF YOU MAY
BE SITTING IN THE FIRST ROW, YOU
APPRECIATE THERE IS MORE CELLS
ON THIS SIDE THAN HERE.
SO CLEARLY THERE IS A
PROLIFERATIVE CAPACITY DIFFERENT
AND BETTER.
SO AGAIN, THIS IS ALL SORT OF
CONTRIBUTING TO THE BIOLOGICAL
BASIS OF THE APPROACH AND YES,
THERE IS -- WITHIN THE
NONHEALING WOUNDS, THERE IS A
SUB SET OF CELLS THAT ARE ABLE
TO RESPOND TO GROWTH FACTORS AND
ABLE TO MIGRATE AND PROBABLY
COMPLETE THE HEALING.
SO, AGAIN, FINDING THAT REGION
AND FINDING THAT DEBRIEFMENT
MARGIN AND DISTINGUISH THE
TISSUE A FROM TISSUE B,
NONHEALING FROM A HEALING
POTENTIAL PHENOTYPE IS REALLY A
BIG QUESTION AND THAT IS WHAT WE
WERE SET TO STUDY AND OF COURSE
OUR WIZARDS LOOKS SLIGHTLY
DIFFERENT AND WOUND HEALING
CLINIC.
THIS IS ROB AND DAVIS AND THIS
IS THE RESEARCH AND CLINICAL
TEAM PUT TOGETHER THAT REALLY IS
TRYING TO FIGURE OUT THESE
BIOMARKERS.
EVERY ONCE IN A WHILE, WE WILL
ACTUALLY GET A SLIDE THAT LOOKS
LIKE THIS AND THAT IS REALLY
QUITE EXCITING.
I'M SORRY THERE IS NOT ENOUGH
LIGHT HERE MAYBE FOR YOU TO SEE.
BUT THE NONHEALING EDGE, THIS IS
THE STAINING FOR BETA CATENIN,
AND WHAT WE ARE LOOKING FOR
NUCLEAR PRESENCE.
NUCLEAR PRESENCE IS BAD.
ABSENCE EVER BETA CATENIN IS
GOOD IN HEALING OUTCOME.
SO WHAT WE DO IS WE STAIN THE
CELLS AND WE QUANTIFY THIS IN A
TISSUE AND REALLY LINK THIS TO
THE CLINICAL OUTCOME AND LOOK AT
THE HEALING, AT WEEK 4 OR THE
BRIEFMENT BIOPSY.
EVERY ONCE IN A WHILE YOU WILL
GET A SLIDE LIKE THIS.
YOU COULD ALMOST DRAW THE LINE
OF THE TISSUE WHERE YOU ACTUALLY
HAVE A LOSS OF BETA CATENIN IN
THE NUCLEI WHICH WILL BE HEALING
POTENTIAL IN THE OTHER SIDE
WHERE WE HAD ALL THE NUCLEI
PRESENT FOR BETA CATENIN.
SO AGAIN, THERE IS THE BRIEFMENT
MARGIN AND I THINK IT'S A MATTER
OF HOW SOPHISTICATED WE ARE IN
FINDING IT AND DEVELOPING THE
RIGHT TOOLS TO REALLY GET THERE.
BUT THAT'S REALLY A GREAT HOPE.
AND OF COURSE, TRANSITION TO THE
GENOMICS APPROACH WE CLEARLY
THAT THE DAY AND AGE MIGHT NOT
BE CLINICALLY FEASIBLE AND
PRACTICAL FOR FEWER EXPENSE --
ASPECTS, BUT IN GENERAL, IT IS
CLEAR THAT CAN CAN SERVE AS AN
EXCELLENT GUIDE TO DETERMINE
WHAT IS A NONHUMAN FROM HUMAN
TISSUE.
AND IF YOU LOOK AT THIS IS THE
PATIENT OR THESE ARE THREE
DIFFERENT PATIENTS BEFORE AND
AFTER THE DEBRIEFMENT AND YOU
CAN SEE THE PROFILES AND THEN
THIS PATIENT OBVIOUSLY HAS
SOMETHING DIFFERENT.
AND IT TURNS OUT THAT THIS
PATIENT WAS NOT BEE REEVED FAR
ENOUGH AND THIS IS A NON-HEALING
PROFILE AND WHEY DID ALL THE
SAME THINGS WHEN WE WENT BACK TO
CHECK THE CLINICAL OUTCOME T
TURNS OUT THAT THAT WAS A
NON-HEALING PATIENT AND THE
SURGEON WENT BACK AND DEBRIEFED
THESE PATIENCE AND REDID MORE
EXTENSIVE DEBRIEFMENT FOR THIS
PATIENT IN ORDER FOR HIM TO GET
TO HEAL.
BUT CLEARLY, IMAGINE THIS IS
KIND OF TO OVERSIMPLIFIED
VERSION, THE PREGNANCY TEST FOR
A WOUND THIS A WAY.
SO YOU COULD USE THE TYPES SAY,
THIS SAY HEALER AND THIS IS A
NONHEALER.
AND OF COURSE WE DON'T NEED BUT
THE BIG MICROARRAY CHIP TO DO
THAT.
WHAT WE ARE TRYING TO DID IS
REALLY NARROW DOWN THE LIST SO
THAT WE CAN HAVE A SMALL STACK
OF GENES THAT CAN ALWAYS TELL
WHEN IS WOUNDED HEALING AND
WHERE THE TISSUE THAT DOES NOT.
AND AGAIN, THIS IS THE -- JUST
TO SHOW YOU THE MARKER THAT IS I
HAVE MENTIONED PREVIOUSLY IN THE
TALK, THIS IS THE EGF RECEPTOR.
IT'S NOT -- THIS IS DOWN
REGULATED AND THIS IS THE
BIOPSY.
YOU CAN APPRECIATE THERE IS A
RESTORATION OF THE MEMBRANE OF
STAINING AND THE SAME THING FOR
THE STEM CELL MARKER WHERE IT
ACTUALLY GETS RESTORED.
NOTICE THESE SLIDES LOOK A LOT
DIFFERENT THAN NORMAL SKIN.
SO WE ARE NOT TALKING ABOUT
HEALTHY TISSUE.
BUT WE ARE TALKING ABOUT TISSUE
THAT HAS A HUMAN POTENTIAL.
AND SO, TO SUMMARIZE THIS PART
IS THAT THE NONHEALING WOUND, SO
WHAT WE ARE CURRENTLY DOING IS
COLLECTING A LOT OF TESTS FROM
PATIENTS AND TRYING TO LOOK AT
HEALING OF A PREDICTIVE MARKER
AND IN NONHEALING WOUNDS, A LOT
OF THEM EITHER DO NOT CHANGE
OVER TIME OR ACTUALLY CHANGE FAR
WORSE, SUCH AS THESE HERE.
AND SIGNAL EARLY TO BETA
CATENIN, WHEN YOU LOOK AT WEEK 0
OR WEEK 4 AND YOU CAN SEE HERE
THE CLINICAL OUTCOME AND
TRAJECTORY OF HEALING.
IT'S NOT IN PLACE.
SO THIS PATIENT CLEARLY IS A
NONHEALER.
NOW, HOW CAN WE REALLY SAY THAT
UPFRONT IS THE REALLY ONE THING
THAT WE ARE TRYING TO FIGURE
OUT.
AND THEN AGAIN, THIS IS THE
PROFILE OF THE HEALING ULCER AS
I SHOWED BEFORE AND AGAIN THE
COMPLETE DECREASE OF ADAM 12 ASK
DECREASE OF BMWR1 AND A DECREASE
OF BETA CATENIN AND LOOK AT THE
TRAJECTORY OF THE WOUND.
IT'S HEALING.
SO AGAIN, DOING SORT OF THIS
APPROACH WITH THE CLINICAL
OUTCOME HAND-IN-HAND REALLY
GIVES US TREMENDOUS POTENTIAL TO
SEARCH FOR REALLY APPROPRIATE
BIOMARKERS.
SO FAR WE ARE NARROW DOWN THE
LIST AND WE ARE IN THE CLINICAL
STUDY WHERE WE ARE TESTING THIS
AND TRYING TO NARROW DOWN THE
LIST AND GUIDE US THROUGH THIS
CLINICAL PROCESS.
BUT I REALLY HOPE THAT WE WILL
HAVE A GENE CHIP FOR WOUNDS
RELATIVELY SOON AND HOPEFULLY
SOONER THAN LATER.
BUT CLEARLY, OUR GOALS ARE,
WHICH WOUND WILL HEAL UPFRONT
AND WHERE IS THE DEBRIEFMENT
MANAGER IN AND AGAIN, WE ARE NOW
USING ALL THE POSSIBLE
APPROACHES.
AND I WANT TO POINT OUT ONE
OTHER THING.
AND THIS IS AGAIN THE WONDERFUL
WORLD OF GADGETS AND ALL
DEVELOPMENTS AND COMPUTATIONAL
MEDICINE IF YOU WANT, THAT IS
HAPPENING RIGHT NOW.
AND I WANT TO POINT OUT MY
COLLABORATION A LONGSTANDING
COLLABORATION THE DOCTOR WHO
DEVELOPED A WOUND ELECTRONIC
MEDICAL RECORD.
HE HAS A RESEARCH TOOL THAT HAS
OR THAT FOLLOWS 132 CLINICAL
VARIABLES FOR EACH PATIENT.
SO IMAGINE HOW WONDERFUL THAT
COULD BE.
SO HE IS FOLLOWING FROM THE
WOUND SIZE THAT IS MEASURED ALL
THE TIME TO EVERY SINGLE ASPECT
THAT IS IMPORTANT AND CLINICAL
TIMING, AND PRESENCE OF
INFECTION AND ALL THE TREATMENT
AND EVERYTHING THAT MIGHT BE
IMPORTANT FOR THE WOUND HEALING.
SO WHAT WE ARE NOW TRYING TO DO
IS BUILD A PLATFORM THAT CAN NOW
SORT OF LINK THIS CLINICAL DATA,
THIS IS DATA THAT CAN BE
EXPLOITED AND IT'S SEARCHABLE
TABLE.
SO MANAGE FIN WE COULD NOW SEE
ALL OF THESE BIOMARKERS AND ALL
THESE THINGS WE ARE DOING FOR
THE TISSUE FOR THIS PATIENT AND
CONNECTED WITH THIS CLINICAL
OUTCOMES AND VARIABILITY HE IS
DOING.
AND REALLY BEING ABLE TO PIN UP
A SUBSET OF PATIENTS AND REALLY
DO A MORE PERSONALIZED APPROACH
RATHER THAN THIS GENERAL SORT OF
GROUPS OF DIFFERENT NONHEALING
WOUND.
AND OF COURSE ONE OF THE APPS
FOR THAT WOULD BE WONDERFUL AND
THAT IS SORT OF OUR GOAL WOULD
BE THAT ONE DAY EVERY CLINICIAN
WHO TREATS WOUNDS WILL HAVE THAT
APP AND IT WILL SEND A MESSAGE
AND SAY OKAY, THERE ARE
BIOMARKERS AND NONHEALING
OUTCOMES COMING.
PLEASE DO WHAT YOUR PROTOCOL
TELLS TO YOU DO.
I THINK THIS IS THE REALITY AND
I THINK WE ARE THERE AND THAT'S
A REALLY GREAT PLACE TO BE.
NOW I WILL JUST A FEW MORE
MINUTES TALK ABOUT A COUPLE OF
APPROACHES OF THE OTHER SIDE.
AND THAT CEREALY THE REVERSE,
HOW TO REVERSE THE FORTUNE OF
THESE CELLS AND OBVIOUSLY WE CAN
CIRCUMVENT THE MISSING SIGNALS
BY DIFFERENT WAYS.
ONE IS USE THINK OF DIFFERENT
APPROACHES AND HI TO SAY, GENE
DELIVER AND ASSETS TODAY ARE
REALLY QUITE WELL DEVELOPED AND
IDEAL SUBJECT FOR THAT SIMPLY
BECAUSE IT'S TOPICAL AND
ESPECIALLY WOUNDS BECAUSE FOR
WOUNDS, YOU DON'T HAVE TO HAVE A
LONG TERM.
YOU HAVE TO HAVE GENE DELIVER
THEY WILL STIMULATE THE HEALING
BUT DOESN'T HAVE TO STAY THERE
THREE YEARS.
IT CAN REALLY BE TEMPORAL.
AND I THINK THAT IS REALLY A
WONDERFUL PLACE TO START REAL
APPLYING GENE THERAPY.
OBVIOUSLY, WE COULD APPLY A LOT
OF DIFFERENT CELLS TO WOUNDS AND
THAT IS THE DIFFERENT THERAPY
THAT ARE AT MOST FDA ARRIVED AND
NEW ONES THAT ARE BEING
DEVELOPED.
SO THEY COULD BE
OBVIOUSLYEE - ON TOL GUS OR NOT
AND OBVIOUSLY DIFFERENT MATRIX.
ALL OF WHICH WILL SIMULATE THE
LOCAL CELLS TO REALLY GET ON THE
PROGRAM THAT THEY KNOW SO WELL
AND EXECUTE THE HEALING.
AND THIS IS ONE OF THE PROJECTS
THAT WE HAVE DONE AND THIS IS
SORT OF DELIVERY OF THE VASCULAR
ENDOTHELIAL GROWTH FACTOR AND
THESE ARE EXPERIMENTS DONE IN
DIFFERENT TYPES OF DIABETES,
WHICH IS TYPE 1 AND TYPE 2.
AND WHAT WE HAVE SHOWN IS IF YOU
HEAT THE MOUSE OBVIOUSLY WITH
ADINOVIRUS DELIVERING VEGF, IT
STIMULATES HEALING AND IT'S, SO
WHAT.
VEGF SIMALATES ANGIOGENIS AND
IT'S EXPECTED THIS WOULD BE THE
OUTCOME.
WHAT WE WERE SURPRISED TO SEE IS
THAT WE HAVE SEEN A TREMENDOUS
EFFECT ON EPIDERMIS.
AND NOT ONLY THAT WOUND HAS
HEALED MUCH FASTER, BUT LOOK AT
HOW MUCH EPIDERMAL LAYERS WE
HAVE HERE.
SO CLEARLY IN IS NOT ONLY
SIMALATES ANGIOGENESIS BUT
EPITHELIALIZATION.
THE OTHER THING ALSO THE
THICKNESS OF THE GRANALATION
TISSUE WHICH IS TREMENDOUS
COMPARED TO THE SAIL LEAN
TREATMENTS OR JUST THE VECTOR
ALONE.
AND THIS IS AGAIN THE CAUSE IN
STAIN TO SHOW HOW WELL THE
COLLAGEN LAID OUT.
SO THIS REALLY TARGETS MULTIPLE
CELL TYPES AND THAT'S ONE OF THE
APPROACH THAT IS IS IMPORTANT.
IF WE ARE USING APPROACH THAT IS
WILL HIT THE SINGLE POINT, IT'S
MOST LIKELY NOT GOING TO BE VERY
EFFICIENT IN THE COMPLEX SCHEME
OF THINGS SUCH AS CHRONIC
WOUNDS.
BUT THERE ARE WAYS WE CAN
STIMULATE MORE THAN ONE CELL
TYPE THEN THEY ALL CONTRIBUTE TO
THE WOUND HEALING, THAT HAS A
VERY, VERY BIG VALUE IN THE
CHRONIC WOUND FIELD.
AND THEN, THE LAST BETA SLIDE IF
YOU WANT THAT LI SHOW YOU, IS
THAT WHAT WE CALL DR.--
(INDISCERNIBLE)
TRIAL.
CLINICIAN SCIENTIST AT THE
UNIVERSITY OF MIME WHOA HAS NIH
STUDY WHERE HE STUDIES CLINICAL
TRIAL OF BONE MARROW PROGENITORS
FOR PATIENTS WITH CHRONIC
WOUNDS.
AND WE KIND OF PIGGYBACK ON THAT
STUDY AND WE COME AND COLLECT
THE TISSUE AND GROW THE CELLS
AND HE DOES THE GREAT STUFF
WHICH IS TREATING THE PATIENTS.
AND ONE THEY THINK HE NEVER
THOUGHT HE WOULD GET, IT TURNS
THOUGHT THEY ARE UNIVERSITY OF
MIAMI, DOCUMENTARY ON STEM CELL
THERAPY HEALING FORCE OF THE
FUTURE.
ASK THEY WON AN EMO IT.
IT WAS ABOUT A CLINICAL TRIAL
AND ANOTHER THEY DO FOR HEART
PATIENTS IN THE STEM CELL
INSTITUTE.
YOU NEVER KNOW WHEN YOU BECOME A
SCIENTIST, MAYBE THERE IS AN
OSCAR IN THE MAKING.
WHAT I WANT TO SAY IS WHEN WE
COLLECT THE BIOPSIES FROM HIS
PATIENTS BEFORE AND AFTER
TREATMENT WITH BONE MARROW
PROGENITORS, WE GROW THESE CELLS
AND THEN WE START FOLLOWING THEM
LOOKING AT DIFFERENT THINGS AND
THEN SHOWING HERE MICRORNA
PROFILES OF THEM AND YOU COULD
APPRECIATE THAT AFTER THE FIRST
TREATMENT, THE RESPONSE IS
ALREADY GOOD IN TERMS OF LOOKING
AT THE EXPRESSION OF MICRORNA21
AND 106.
BUT 16 IS STILL THERE.
AND YOU KIND OF GET EVERYTHING
IN ORDER AFTER A SECOND
TREATMENT.
BUT WHAT THIS TELLS ME IS THAT
THERE MIGHT BE A WAY OF WHAT I
CALL, ORDERED RESTORATION.
SO CLEARLY, YOU DON'T HAVE A
MAGIC BULLET WITH EVERYTHING
GOES BACK TO NORMAL.
BUT THERE IS A SEQUENCE OF
EVENTS THAT CAN ACTUALLY LEAD TO
A HEALING PROCESS, WHICH IN A
WAY, WHAT I TOLD BUT SWITCHES,
MAY BE TELLS US THAT WE CAN
ACTUALLY REVERT THESE NONHEALING
CELLS SLOWLY BUT SURELY THROUGH
THE PROCESS BECOME A HEALING.
AND I DIDN'T EACH TOUCH UPON
THESE PROGENITORS BECAUSE THAT
TECHNOLOGY CLEARLY GIVES A
TREMENDOUS OPPORTUNITY ALSO IN
THE CHRONIC WOUNDS AS MANY OTHER
CLINICAL DISCIPLINES, BUT THAT
IS AGAIN ANOTHER POTENTIAL OF
HOW WE CAN REVERSE THE NONHUMAN
CELLS INTO A HEALING CELL.
SO IN SUMMARY, I WILL NOT READ
IT, BUT IN GENERAL, WHAT I HAVE
TOLD YOU IS THAT GENOMICS
APPROACH IDENTIFIED NONHEALING
WOUND PHENOTYPE AND WHAT WE
LEARNED ABOUT IT IS THAT THERE
IS INHIBITION OF CELLULAR
MIGRATION AND LOSS OF
APPROPRIATE SIGNALS CONTROL
GROWTH FACTORS AND OBVIOUSLY
LACK OF DIFFERENTIATION IN THE
EPIDERMIS OF NONHEALING WOUNDS
AND WE HAVE ALSO FOUND THAT
THERE IS DISTINCT POPULATION
WITHIN THE CHRONIC WOUNDS THAT
HAS A HEALING POTENTIAL AND THAT
IS LINKED TO CLINICAL OUTCOMES
IN PATIENTS AND THIS LOSS OF THE
SIGNALS OF CONTROL AND ARE
REALLY NOT ONLY COMING FOR WHAT
WE KNEW ALREADY ABOUT HIGH PROAS
PROTEASE ACTIVITY BUT ALSO
DECREASE OF RECEPTAUTHORITIES
MANY ARE SIGNALING MOLECULES
THAT MANY OF THE SIGNALS IN THE
CELL AND I'LL JUST INCREASE IN
MICRORNA MOLECULES.
AND OBVIOUSLY ONE APPROACH WOULD
BE TO REALLY DEBRIEF THE CELLS
AND RESTORE HEALING PHENOTYPE OR
THE OTHER SON TO REVERSE THEIR
FORTUNE.
AND I THINK THAT THIS IS -- I
HAVE TO SAY PROBABLY MOST
EXCITING TIMES IN BIOMEDICINE
BECAUSE I THINK TECHNOLOGY THAT
WE HAVE IN OUR HANDS ARE SO
TREMENDOUS THAT WE ARE YET TO
LEARN HOW TO REALLY NEUTRALIZE
THE ADVANTAGE OF OUR PATIENTS
AND I THINK THE GOOD DAYS ARE
COMING IN MANY WAYS AND I'M
REALLY, REALLY EXCITED TO BE A
SCIENTIST AT THIS TIME.
AND WITH THAT, I HAVE TO SAY
THERE ARE A LOT OF PEOPLE I HAVE
TO THANK.
AND IT'S IMPOSSIBLE TO LIST THEM
ALL.
I HAVE BEEN PRIVILEGED TO REALLY
WORK WITH EXTRAORDINARY SET OF
PEOPLE IN EVERY SITUATION.
I HAVE BEEN IN MANY OTHERS
BECAUSE TODAY COLLABORATIONS ARE
THE KEY.
AND I WILL HAVE TO THANK
OBVIOUSLY, PEOPLE IN MY LAB.
THIS IS FAIRLY ACCURATE PICTURE
AND YES, THIS IS MIAMI.
I'M SORRY, YES, WE DO HAVE FUN
OCCASIONALLY.
AND THEN OF COURSE THE
UNIVERSITY OF -- UMASS WOUND
CENTER.
AND OBVIOUSLY, NIH, BECAUSE
EVERYTHING I SAID TODAY REALLY
WAS FUNDED EXCLUSIVELY BY NIH,
ALTHOUGH I DO HAVE OTHER
PROJECTS THAT ARE NOT, BUT
EVERYTHING I SAID TODAY REALLY
COMES FROM THAT INITIAL GRANT
FROM NATIONAL INSTITUTES OF
NURSING RESEARCH THAT REALLY
SORT OF RETAINED ME IN A WOUND
HEALING.
IT WAS T. WASN'T MY FIRST RL1.
BUT IT WAS MY FIRST IN THE WOUND
HEALING AND REALLY I HAVE TO
THANK THEM FOR REALLY SORT OF
SHEDDING THE LIGHT ON THAT PATH
AND KEEPING ME IN THAT FIELD.
AND OF COURSE, MOST IMPORTANTLY,
THANKS TO ALL OF OUR PATIENTS
BECAUSE THEY ARE REALLY SPECIAL
AND I'M REALLY HOPING WE MIGHT
NOT HEAL THE WOUNDS OF THE
ENTIRE HUMANITY BUT CHRONIC
WOUNDS WE HOPE TO BE VERY SOON.
THANK YOU VERY MUCH AND I'LL
TAKE QUESTIONS.
(APPLAUSE)
>> THANK YOU VERY MUCH.
WE DO HAVE TIME FOR A FEW
QUESTIONS.
IF YOU WILL TAKE THE MICROPHONES
ON THE SIDE AND SAY YOUR NAME.
WE CAN STEP UP TO THE MICS.
>> CONGRATULATIONS FOR EXCELLENT
COVERAGE AND EXCELLENT WORK.
SO YOU IDENTIFIED QUITE A FEW
INTERESTING TARGETS.
SO HOW MANY OF THEM YOU THINK
YOU MIGHT BE ABLE TO USE IN THE
PATIENT CARE AND ALSO WHAT IS
THE -- PART TESTIFY THAT
ARRANGED THIS PROCESS OF
DEFECTIVE WOUND HEALING?
>> SO THERE ARE TWO DIFFERENT
QUESTIONS IN THAT QUESTION.
ONE IS RIGHT BEFORE THESE 1500
POSSIBLE TARGETS.
SO WHAT WE FOCUSED IS MAINLY
TRYING TO IDENTIFY THE POTENTIAL
BIOMARKERS THAT WILL PREDICT THE
OUTCOMES OF HEALING.
BUT APART FROM THAT, THERE ARE
LOTS OF DIFFERENT POTENTIAL
TARGETS THAT WOULD BE VALIDATED
AS A TARGET -- PHARMACEUTICAL
TARGET.
BUT THE ISSUE WITH THAT IS
REALLY, YES, ANSWERING THE
QUESTION VERY, VERY SHORTLY,
THERE ARE A SET OF TARGETS THAT
CAN BE USED, FOR EXAMPLE THESE
MICRORNAs.
AND I MEAN THEY ARE MAJOR
REGULATORS AND THEY CAN BE
TARGETED BECAUSE THEY REALLY
REGULATE A LOT OF WHAT IS
HAPPENING.
SO THEY WOULD BE THE OBVIOUS
TARGET.
BUT I THINK FROM THE
MICROARRAYS, IT DOESN'T POINT
OUT A SINGE SET OF TARGETS.
IT TELLS YOU MORE ABOUT WHAT IS
GOING TO IN MOLECULAR AND
CELLULAR LEVEL.
AND REALLY UNDERSTANDING HOW THE
CELLS OR TISSUE GOT THERE WOULD
BE REALLY IMPORTANT AND THAT'S
WHERE THEY ARE TREMENDOUSLY
VALUABLE.
THAT'S WHERE THE TARGETS ARE.
BECAUSE WHEN YOU TAKE A BIOPSY
OF A NONHEALING WOUND, THAT IS
IF YOU WANT AN END POINT, THAT
TISSUE IS NOT HEALING.
BUT WHAT WE STILL DON'T KNOW IS
HOW THE PROCESS REALLY SORT
OF -- IF YOU TURN BACK THE TIME
OF THE ORIGIN WHEN THOSE CELLS
ACTUALLY PROGRESS TO THE
NONHEALING.
I THINK THAT WOULD BE REALLY
IMPORTANT TO UNDERSTAND.
AND THAT IS SOMETHING THAT WE
ARE WORKING ON, REALLY TRYING TO
FIND OUT WHAT HAPPENED BEFORE
THEY ACTUALLY GOT TO BE
TERMINALLY NON-HEALING SO TO
SPEAK.
DOES THAT ANSWER THE FIRST PART
OF QUESTION?
IT IS REALLY, YOU KNOW, IF YOU
ASK ME, IS THERE A MAGIC
MOLECULE, THERE ISN'T.
THERE REALLY ISN'T.
AND THE CHRONIC WOUND, I DON'T
THINK THERE WILL BE A MAGIC
MOLECULE.
A SINGLE ONE DEFINITELY --
DEFINITELY NOT.
IT'S THE COMPLEXITY OF THE
DISEASE AS SUCH IT'S NOT
POSSIBLE.
I FOUND LIKE MY REVIEWER.
IT'S VERY SIMILAR AND SOME WOULD
BE HERE AND WILL GO AND PROVE ME
WRONG AND I WILL HAVE NOTHING
MORE THAN THAT.
BUT WHAT I WANTED TO SAY IS THAT
YOU ASK -- ANOTHER THING ABOUT
THE DIABETES.
AGAIN IN DIABETICS, THERE ARE
MULTIPLE COMPONENTS.
METABOLIC SAY VERY IMPORTANT ONE
BUT THE OTHER ONE THAT GOES WITH
THAT DIABETES IN DEVELOPING
CHRONIC WOUNDS, THERE ARE A
COUPLE OF THINGS.
ONE IS PERIPHERAL NEUROPATHY.
PATIENTS LOSE A SENSATION IN
THEIR FEET AND THAT REALLY
CONTRIBUTES IN PART -- NOBODY
REALLY KNOWS.
WE STILL DON'T KNOW AND PINPOINT
HOW MUCH THIS NEUROPATHY REALLY
PLAYS A SCROLL HOW MUCH DIABETES
THEY ARE LINKED TOGETHER.
I COULD TELL YOU ONE THING,
THERE ARE SETS OF PATIENTS THAT
DEVELOP PERIPHERAL NEUROPATHY.
THEY DON'T HAVE DEBATIES BUT
THEY COLORED SIMILAR CONIC
ULCERS IN THEIR FEET.
DIABETES PREDISPOSE SYSTEM
BECAUSE OF OBVIOUSLY METABOLIC
ASPECTS BECAUSE OF LOSS OF
ABILITY TO FIGHT INFECTIONS AND
THERE ARE A LOT OF OTHER ASPECTS
OF DIABETES THAT KIND OF PLAY A
ROLE OF WHY THE TISSUE IS NOT
HEALING.
BUT THERE HAS TO BE SOMETHING
LINKED TO THE LOCAL TO THE FEET
AND LOWER EXTREMITIES.
IF YOU REALLY LOOK AT THE WOUNDS
AND SURGICAL WOUNDS ON THAT,
THEY ACTUALLY HEAL, MAYBE SLOWER
BUT THEY DO.
SO IT'S NOT, *** SAY IT'S NOT
COMPLETE DISABILITY OF HEALING,
OBVIOUSLY DIE BEAT CEASE A BIG
PART TESTIFY.
WE HAVE DONE EXPERIMENTS TO SHOW
THAT YOUNG DIE BEATIC MICE DON'T
HAVE, THAT MUCH OF IMPAIRMENT
AND HEALING COMPARED TO THE AGE
THAT THIS WAS MIND.
IF YOU THINK ABOUT, IT IS ALWAYS
SOME UNDERLYING COM PONE THAT HE
WENT PLAYS A ROLE IN ADDITION TO
THE DIABETES THAT PLAYS A ROLE
IN DIABETICS.
>> GOOD LUCK IN THE CHALLENGING
AREA.
>> THANK YOU.
>> ONE MORE QUESTION.
>> THANK YOU VERY MUCH.
THANK YOU FOR YOUR PRESENTATION.
I WAS CURIOUS, DOES HIGH GLUCOSE
CHANGE THE DIFFERENTIATION
AND --
(INDISCERNIBLE).
>> WE HAVE DONE THIS IN
SCHEDULEATURE AND I HAVE TO SAY
I HAVEN'T SEEN ANY EFFECT IN
CULTURE BUT OBVIOUSLY THAT
DOESN'T MEAN MUCH.
BUT I CAN TELL YOU THE
EXPERIMENTS THAT WE HAVE DONE IN
THE MICE THAT IS PUBLISHED, IN
EXPERIMENTAL DERMATOLOGY.
AND IF YOU LOOK AT THE MICE, THE
YOUNG DIABETIC MOUSE CONTROLLED
OR UNCONTROLLED DIABETES.
IF YOU LOOK AT NORMAL HYPER AND
HYPOGLYCEMIC, YOU REALLY DON'T
SEE A TREMENDOUS DIFFERENCE IN
WOUND CLOSURE CAPACITY OF ON
THESE MICE.
THEY ARE ALL THE SAME.
IT DOESN'T MEAN THEY ARE GOOD
BUT TA DOESN'T OBVIOUSLY AGAIN,
WE ARE TALKING ABOUT MICE AND
EXTRAPOLATING, I WOULD REALLY
HAVE TREMENDOUS ACTIVITY DOING
IT.
I THINK IT'S IMPORTANT TO
UNDERSTAND THAT IN AGING IT
BECOMES A PROBLEM.
SO AGAIN IT'S A COMPONENT THAT
REALLY -- OF AGING IN
COMBINATION WITH DIABETES IN THE
CONTEXT OF MICE.
WE ABSOLUTELY SEE THE
DIFFERENCE.
BUT NOT IN THE GLUCOSE LEVEL.
>> THANK YOU.
(APPLAUSE)
>> THANK YOU VERY MUCH.
I WOULD LIKE TO INVITE YOU TO,
WE HAVE A RECEPTION FOLLOWING
THIS TALK IN THE NIH LIBRARY SO
AS YOU EXIT THE AUDITORIUM, TURN
TO YOUR LEFT AND YOU'LL SEE IT
IS RIGHT THERE.
WE CAN CONTINUE THE CONVERSATION
THERE.
AND THE RECEPTION IS SPONSORED.