- I'm Dr. Nelson Scottsdale.
Welcome to the fourth day of the 42nd Annual Darwin Festival
here at Salem State University.
And what I'd like to do now is turn the webinar
over to my colleague, Dr. Sheila Schreiner,
who will introduce today's speaker.
Thank you very much.
- Good morning, before I introduce this morning's speaker,
I just wanna remind the audience
of a couple of housekeeping items.
If you do get kicked out of the webinar,
you can use the same link that you used to enter to rejoin.
Also, we're gonna hold questions until the end,
but you are more than welcome to ask questions
through the Q and A function that's found on the bottom bar.
Okay, so you can enter those questions in
at any point during the presentation,
but again, we will be holding those till the end,
till our speaker has concluded their presentation.
Lastly, there is closed caption available.
So if you click the link for live transcript,
you can turn that on or off.
Okay, so I have the honor of introducing,
actually, a classmate of mine from grad school.
Our speaker is Dr. Cecelia Yates.
She's an associate professor
at the Department of Health Promotion and Development,
which is part of the School of Nursing
at the University of Pittsburgh.
She also holds a secondary appointment
for the Department of Pathology in the School of Medicine
at the McGowan Institute of Regenerative Medicine.
Dr. Yates attended to Tuskegee University
where she earned her BS in Biology and Chemistry.
She then obtained her PhD at the University of Pittsburgh,
where she was a classmate of mine.
Over the past 15 years,
she has experience in fibroblast, chemokines,
and extracellular matrix biology
in the pathogenicity of organ fibrosis.
Her research focuses on the understanding of immune cells
and stromal cell mediated interactions to contribute
to the pathogenicity of fibrotic diseases
such as scleroderma and IPF.
Her research group combines both translational
and clinical models to develop therapies,
including biometric peptides, cellular transplantation,
and bio reactive scaffolds to promote tissue regeneration.
She's also a co-founder and a chief scientific officer
at FibroKine, which is a Pittsburgh-based startup
that is developing broad spectrum anti-fibrotic
chemokine peptides to treat organ fibrosis.
So with no further ado,
I will turn it over to Dr. Yates.
- Thank you for that very kind introduction
and the invitation.
I am very excited to present at this festival.
When I began to read a little about it,
I think it's an amazing
festival and efforts that you all are putting together,
you have put together over the years
and I'm happy to be a part this year.
So,
as she mentioned, I have a few,
I guess I can, there we go.
I have a few disclosures that are relevant to this talk.
At the end I will start mention some of the technologies
that we recently developed that are introduced
in the middle of being commercialized,
so I wanna disclose that.
And the overall objective of my talk today
is to really teach you a little bit,
for those who don't know about some of the intrinsic
processes that are involved in tissue repair,
not just in skin but multiple organs.
All organs have the capacity, well most organs I should say,
have the capacity to repair itself.
And I want to kind of walk you through
how we take something at the bench
and start investigating a mechanism,
really the origin of something, our molecular process,
and how we move that forward and translate that
to have impact on patient care
and the development of therapeutics.
So I'll describe the tissue repair process
and the role of chemokines.
I'll tell everyone all about what chemokines are,
for those who don't know.
And we'll talk a little bit about the crosstalk
between cellular functions that happens
during this dynamic process of tissue remodeling.
And I'll describe a translational approach
to the development of therapeutic drugs.
And then I'll summarize the functions
and the cellular dysregulation that leads
to identifying potential targets for treatment.
So if we think about, let me move on here,
when we think about the healing process, right,
healing is a physiological response to trauma.
And that trauma can be very insignificant
where sometimes we don't even know that there is a trauma,
or it can have a major impact
on our different organ systems.
But regardless of that, it usually initiates
a complex pathway of biochemical events and cellular events
that secrete different growth factors and cytokines
in the development of re-establishing the tissue
that was damaged.
And as I mentioned, all tissue,
just about all tissue has the capacity of repairing,
it can be damaged.
And so this is just kind of an overview
to really orient everyone into the impact.
Often I mentioned in talks
that over 45% of deaths
in the U.S. are a result of fibrosis.
And people argued and say, "oh no,
there's cardiovascular disease, there's cancer."
And yes, but ultimately the comorbidity
or the cause of death is organ failure
due to excessive remodeling or fibrotic insult.
And so it is a major issue in itself.
It's a disease but it also contributes,
it also is classified as a comorbidity.
But when we think about uncontrolled healing,
there are three classes
that I want to orient everyone on.
And that's fibrotic wounds,
excessive healing and chronic wounds.
Chronic wounds are these non-healing wounds.
We most are familiar with them in diabetic ulcers,
the venous ulcers or pressure ulcers.
And there are over 6.7 million people
who are suffering from non-healing wounds, chronic wounds.
Okay, then there is tissue injury, right?
So I explained the type of wounds,
but let's talk about the tissue injury.
In my group we focus on
very specific types of injury.
One, as I mentioned,
the chronic wound as we see in a diabetic ulcer.
Also, progressive fibrosis,
this is excessive remodeling of the tissue
due to an autoimmune insult.
Hypertrophic scars, which can be induced by burns.
And lung fibrosis, it can be introduced by autoimmune
or other genetic factors.
Even myocardium fractions after a heart attack,
the myocardium continues to remodel.
And clinicians have done really well at saving folks.
They've made major advances to saving folks
from the heart attack,
but ultimately, the mobility and mortality
comes from the continued remodeling of the heart.
And so our mission is to really dissect
and understand molecular processes that contribute to these
and what are some of their underlying causes,
but also where they overlap.
And look at those processes
and see if we can develop or find targets.
So over the last 15 years,
one of the targets that I have been most interested in
is looking at chemokines.
And so I'll kind of describe the healing process
and then go into what a chemokine is.
I think I'm automatically going,
yeah, there we go.
So the healing process is one that is orchestrated
at the time of insult,
whether it's a insult to the skin
where you have a denuded area,
or if there is a insult or like inflammation
or some type of injury to the underlying tissue
that also initiates the healing process.
And so, when we think about healing,
it's typically classified into three separate phases.
You may hear it's classified in four,
but they are overlapping phases.
But they're not mutually exclusive
in the sense that this dynamic process is going on
almost simultaneously in some parts.
And it mirrors that of what we see in developmental biology,
they are some of the molecular elements of development.
And so hemostasis and inflammation,
it's usually depositing the fibrin matrix
back into the wound.
There are cells that neutrophil and your macrophages
your immune cells that come in
and really help repopulate and restore order.
If it is a open wound,
it helps clear the debris and infection.
If it's a closed wound,
it helps to begin to initiate other cells to enter
into the remodel, the injured area,
but also reduce the inflammation,
remodel, heightening the inflammation,
and then subsequently reducing inflammation.
And so there's also tissue repair or tissue replacement.
This is also sometimes called
the provisional remodeling phase
in which the matrix is then being formed.
And so now you have more of your stromal cells come in,
sector fibroblasts, and your endothelial cells
that want to repopulate or reestablish the integrity
of the tissue.
But if the tissue was damaged in such a way
that now the matrix and connective tissue
are no longer functional for the particular organ,
the fibroblast, the endothelial cells play a major role
in coming in to help repopulate and restore order.
And so this is at the same point in which we began to see
a decrease in normal healing.
A decrease in inflammation,
so the inflammation begins to resolve.
And then last, there is a contraction or remodeling
where everything is reorganized
and there's a realignment of the tissue.
So ultimately there's minimal scar.
After birth, there is the all scar from all injury,
there's really no scarless injury.
We do see scarless injury in fetal tissue,
which gives us some insight into how development
could play a role, understanding how development
can play a role in helping us reduce scar as we age.
But at this point, there will be a minimal scar
after injury during normal healing.
But what is the pathological state and have most concerned
is when there is excessive or there's a failure to heal.
And we like to classify this as a failure to start,
which is the chronic wounds, and then a failure to stop,
which is also considered excessive healing.
So if I can just briefly walk you through
some of the general elements of this is,
if you look at the fingertip there
everyone has had some type of minor injury,
we call it a superficial injury,
and this is just a nice dramatic image
to kind of get everyone on the same page.
But you have the bleeding, it clots.
Then there's the scab,
and this is where there's that interplay
between the fibroblast and the macrophages,
they're trying to restore homeostasis
by increasing the inflammation, but also getting rid
of all of the debris and any passages that may have entered.
And then, we move into the proliferative phase
where the fibroblast need to repopulate that tissue.
Sorry, I'm trying to move my, there we go.
We need to repopulate that the tissue.
And then there's a nice layer that is covering
or that will restore at least the outer layer,
the one that we can grossly see will be healed.
And if everything goes well, the underlying tissue
which we consider the dermis will be healed as well.
But in chronic wounds, this doesn't go that way.
There is a persistence of healing.
And in fact, it's really stalled in between the inflammation
and proliferative phases in our remodeling phase.
And in some cases, chronic ones can be so severe
that patients are seen in the clinic multiple times a week
for years to constantly be debriefed and to remove
the dead tissue in which this wound is failing to heal.
And then there's the excessive wounds.
And it's also could be progressive.
What I'm showing you here is, oops!
That's a...
That should have been removed.
But I'm showing you here is a liver fibrosis
in which the liver has a insult,
in this case it's fatty liver.
And or it could be a viral infection,
and initiates the fibrosis and then the liver begins scar.
Now the liver happens to be extremely regenerative organ,
and it turns over constantly, but in some cases
such as fatty liver that is caused
through multiple insults, the fibrosis outweigh,
doesn't allow for appropriate regeneration.
So, just to kinda tell you, like,
I kind of give really basic science and general overview
of the healing process, but it's not that simple.
And this is sort of a play, one of the first in my lab,
did this really nice diagram.
Well, when we were thinking about how "The Game of Thrones"
kind of, really what's going on
and how the interplay between the fibroblasts
and the macrophages and other cell types,
also the molecules, the secreted factors
that they are secreting.
All of this is going on and it's such a dynamic process,
it's really who wins is gonna really determine the fate
of the overall healing.
And what we have recently seen is that who wins
is or who outsmarts the other cell type,
or what cell type dominate really does dictate
the underlying pathology of the wound
and ultimately the long-term trajectory.
So what I'm describing to you is the process
that has been well-described.
It was initially described by a well-known scientist,
Nina Disel, and her focus was really on oncology .
and in cancer biology.
But it's called dynamic reciprocity.
And dynamic reciprocity is really the origin
of how behavior changes.
And what it describes is that there's this interplay
between all facets of the tissue from the single molecule,
the structure of the tissue,
the cells,
the secreted factors, all of these things actually interplay
with each other to directly dictate the behavior.
And this type of cell cell, cell matrix molecule,
cell autocrine, paracrine signaling
is what makes the tissue repair process.
It's freely dynamic, but it's also been a major challenge
for scientists to understand what element to actually treat.
And so what I have been interested in
is looking at chemokines, the role of chemokines.
So what are chemokines?
Chemokines are small cytokines,
and they are extremely versatile,
most have multiple functions.
Some are very ubiquitous in nature
in which they can be expressed in multiple cell types,
but function either in parallel, but also in opposition.
And which I will describe to you a bit.
But when we look at that, this is kind of a broad element,
but when we look at the involvement of chemokines
in cellular and biological processes,
it covers a very wide net from cell differentiation,
endocytosis, immune cell development to respiratory burst,
structure and function of the cells,
apoptosis, and then even cell movement.
Originally, if you know, when I first started in this
chemokine first sort of new on the scene
and they were all thought to be major players
and immune or inflammation regulated processes.
What we now know is that they play a much broader role.
Yes, they are key in initiating or continuing
the chemotactic insult or allowing cells to come
or even halt into the injured area.
But equally, they play a role in modulating
how our stromal cells, like our fibroblast
produce the matrix to develop,
and the connective tissue to restore the integrity
of the tissue.
And so we have really focused our work over the last
10 to 15 years on trying to understand
how they can simultaneously modulate inflammation,
but also matrix for modeling in the setting
of a injured tissue.
And so this is just to show that chemokines
are widely known to be biomarkers,
and noted to be dysregulated in a host of diseases,
so this is just kind of give you an overview
of the different organ systems in which they are involved.
I've highlighted the ones that we're gonna discuss today.
And those are of excessive healing,
constitutes what we see in myocardial infractions
scleroderma, IPS, and also fatty liver disease.
So going back to the overview process
that I mentioned earlier in which inflammation
is the initial stage and there's a recruitment itself,
this is where chemokines come in.
And they actually play a role in allowing the platelets
to release neutrophils to release and be recruited.
And they are,
simultaneously at this stage,
promoting the persistence of angiogenesis.
Their involvement in the proliferative phase
stretches from the neovascular support
of cellular proliferation and migration,
also involved in the
re-epithelization of the epidermal layer
is which we see in skin.
They really help, aid and stimulate macrophages
to polarize and enter into a different phenotype
in which TGF beta are released to become
until they're in a more pro-fibrotic profile.
And they also are play a major role
in the initiation of
what we consider fibroblasts,
differentiation into myofibroblasts,
which are these more contractile
or fibrotic fibroblasts type of classification.
And so when there's this imbalance or disagree,
there really is this sort of battle
between the roles that the chemokines are playing
and how they will interact with the different cell types.
Because the same chemokine and their receptors
are expressed widely on multiple cell types.
And they're secreted equally by multiple cell types
in the wound setting.
And this does cause, it oftentimes, this imbalance
and this imbalance is what we see
that develops the pathological state of fibrosis.
And then the case that I'm gonna describe today
in skin fibrosis, what we see is that the imbalance
and these metallic proteases,
which are these tissue
degradation proteins
that we see in their inhibitors when it causes that
there's like a stoichiometric imbalance,
there isn't that is lost.
This is when we see a persistence in tissue remodeling,
that ultimately ends in fibrosis.
And if that fibrotic state, if that imbalance is unchecked,
then the organ ultimately fails.
There's a potential case to be made
that because they're so widely expressed
and they're so ubiquitous, that the chemokines
could potentially be a target for in treatment.
And so for the rest of the talk,
I am gonna try to make that case to you
by focusing in on two cell types that are of most interest
to us and that are key players in the healing process.
And that's the macrophage and the fibroblast.
So, as I mentioned, macrophages are these immune cells,
they're extremely versatile by phagocytose.
They play a major role in inflammation
but also helping restore homeostasis.
They can polarize, and,
I won't get into
the deep immunology of the classifications
of their levels of polarizing,
but we do know that these cells polarize on a spectrum level
and into a different phenotype in which they can go
from being really pro-inflammatory to anti-fibrotic.
So these are very dynamic cells.
On the other hand, there are the stromal cells
that I mentioned or the fibroblast equally,
very versatile cells, they can differentiate
and become proliferative, and if they migrate
and then they go into this reactive state.
What you're seeing here is a uniphasic image
of fibroblast in their reactive state
where they are expressing transcription factor,
alpha-smooth muscle actin, and we can see
that they're becoming contractile,
and this is when they will start synthesizing
the matrix that is needed to repopulate the injured area
or remodel the injury area.
So, macrophages and fibroblasts are tissue resident cells
in the skin.
And so they're going from, well,
the fibroblast are going from a quiescent state
to this reactive state, which we consider
active fibroblasts, or even in some cases
can be a fibrotic fibroblast.
And in which case they're matrix producing function
is tightened, and they begin to secrete matrikines
such as tenascin and laminin and collagen.
And in the manner in which they secrete them,
it really dictates the overall mechanical properties
of the wound bed, and also the integrity of the wound.
Here, where I'm showing you is CXCR3,
which is a chemokine receptor to CXCL10.
And earlier we have shown, and others have shown
that CXCL10 is a stop signal for these fibroblasts,
it shuts off the matrix-producing function
of the fibroblasts.
It inhibits their motility.
It even blocks the motility, well known
motility inducer,
and fibrotic initiator of TGF beta.
On the other hand, these macrophages
which we, these initial macrophages,
they're also tissue resident cells,
but when they become very,
have this heightened inflammatory phenotype,
they're classified as M1 macrophages,
and they actually secrete and express
CXCR3 but also secrete high levels of CXCL10.
They at this stage, they're extremely migratory
and proliferative, but yet when they switch back
to more the resolving phage, which we classify as M2,
the expression and the secretion of CXCL10 is lost.
And so what I'm trying to convey to everyone
is that there's this yin-yang, this imbalance,
the fibroblast in CXCL10 will stop
and halt it's initiation and progression
of continuing to induce this fibrotic state into the tissue.
But on the other hand, in the macrophages
it's promoting motility,
it's promoting increased inflammation
or sustained inflammation through multiple pathways.
It is interfering gamma induced,
and this is what we're kind of showing here.
And so it does go through
the cascade of events,
and so we see it's full in compliment,
we see it's role in innate as well as adaptive view.
So we think that the life of macrophages and fibroblast,
although widely considered to date
as two separate class of cells, have more in common
than we in the community have initially realized.
And in fact, they work in concert with each other,
they're sort of silent partners.
And so there were a couple of questions
that we've been asking, is like really what instructs
the fibroblasts to adapt a pro-inflammatory phenotype?
So these fibroblasts can, as I mentioned,
when they're secreting these chemokine,
we have profiles that we've done in genomic
and proteomic profiling, and found that they really do have
a pro-inflammatory signature at different stages
in the healing.
They could be pro-wounding and they could be pro-fibrotic.
But then also, they can,
especially when they're highly expressing
the CXCL10 chemokine,
they can reveal
a more anti-inflammatory, anti-fibrotic
and pro-resolving profile.
So how is this possible and what is the appropriate balance
or what are the modulators of keeping this imbalance
in play to allow the pathology
or the pathological state of fibrosis to continue?
Or the other question is,
what is the environmental influences
that contribute to that?
And so we have postulated that there really is this cyclic
element to healing that involves this back and forth
between macrophages and fibroblasts in a fibrotic state.
And in each case, the activated fibroblast can also
perpetuate the inflammation by being pro-fibrotic.
And in the macrophage, on the other hand,
can continue or
sustain the pro-fibrotic state
by being pro-inflammatory.
So I'll walk you through just one,
experimental system that we've used
at the bench in which, we wanted to,
kind of test our hypothesis about the interplay
between fibroblasts and macrophages.
We really wanted to look at, their autocrine signaling
as well as the pair Quinn signaling
between the two in the Jackson green signaling.
And so in this next one
we've taken both narrow derived monocytes.
They have been polarized with appropriate simulators
to reveal the phenotype of a monocyte or a M1,
or M2 macrophage.
We've taken skin fibroblasts as well.
And we've either induced them
with a pro-inflammatory factor TNF alpha
or a pro-fibrotic factors, I mentioned before to TGF beta.
And the downstream analysis that I'll kind of go through,
if we've done functional analysis on those protein profiling
and transcriptional profiling.
But to give you overview we look transcriptionally
and we wanted to characterize the secretome
and matrisome of these cells
due to the crosstalk when these cells are cultured together
in a Transwell.
So there's this, this pair Krantz signaling
that we were trying to identify.
We were able to see that the macrophages differentially
alter the fibroblast secretome.
And so the fibroblast had this,
anti inflammatory secretome,
and when they were induced
or co stimulated with, in one macrophages
we see increase in TNF alpha, pro-inflammatory cytokine
with the increase in TNF
interfering gamma CXL10
and IO1 beta.
So this pro-inflammatory profile is conceived.
And then the macrophages also difference
is for us the matrix tone, right?
So now we're looking at the matrix
and the M1 interestingly, while we see there,
the causal effects of them,
inducing a pro-inflammatory product profile
in the fibroblasts, it had a anti-fibrotic effect.
So what we're showing here is decline,
which is a anti-fibrotic matrikine or matrix protein,
and that's increased where pro-fibrotic matrikines
such as collagen, one and two, matrixyl
are increased with the addition of M2.
So what does that tell us, right?
That the relationship is complicated one,
but also that, if we think about this in the context of
the tissue remodeling and the pathological state remodeling,
they are actually, the theory or
the concept of dynamic reciprocity is at play here.
And that is where the, one cell type
is actually initiating an alternate phenotype,
which is unfavorable in this case and the other
and is perpetuating a cyclic event.
And it prevents the overall resolution
or resolving of the tissue.
And so we've even gone back and, taken those data and,
things that we've seen at the bench
and tried to see if we can change this
in the initial settings
we can actually alter or change the trajectory
by inducing a specific phenotype of macrophages
into the wound bed, during the healing response.
And so that's what we did here.
We induced,
we created an injury in the animal
and we either added M1 or M2 fibroblast,
M1 or M2 macrophages with the fibroblasts.
So this was what we consider a cell therapy
or a transplant in there.
And so the overarching conclusion that I want you to
kind of see here, is that with the M2
as I mentioned previously, what we saw in our
in these studies is that it introduced
this pro-fibrotic fibroblast phenotype
and the M1s are less, had it more of an anti-fibrotic.
And so what I'm showing you
on the bottom panel is 30 days post healing
where we can really evaluate the alignment
and the integrity of the tissue.
And so this is a picrosirius red staining.
And what we do is we image these
under bio forensic polarized light to really assess
the collagen content or the collagen types.
We can differentiate between collagen one and three,
mature and immature collagens.
But also look at the alignment of the tissue
which really gives us some close
or understanding our assessment
of the overall fibrotic state of the of the organ.
And what we see is that with M1 as expected,
where there's anti, we see increase in decrinal
or anti fibrotic molecules, the alignment is more in order
of what we consider organized.
And with the M2, we see higher levels of collagen one
wanting to lessen and fibronectin
and we see this bright red which signifies disalignment
and a thickening of the tissue
but also just organization.
And so this can be quantified in multiple ways
but we use frontera transfers to quantify this,
to confirm that there is a long-term effect of these outcome
to altering the wound trajectory by failure to transplant.
So we can change the trajectory of a potential wound
by introducing specific cell phenotypes.
So since we are able to do that, I wanted to step back again
and look at how the chemokine of interests
and that we see in both macrophages and the fibroblast
that are functioning in a ubiquitous nature, plays a role.
And so we did similar studies using the CXCR3
which is the receptor for CXCR10,
knock out animals cells, mice, as well as their cells.
And the interesting thing we found was
that when you remove the ability for the M1 to express
or signal the CXCR10 to CXCR3
that macrophage simulation
of fibroblasts is completely changed.
And in fact, CXCR3 is required on the macrophages
for the fibroblast to simulate that pro-fibrotic response
that pro-inflammatory response that we see in the fibroblast
and the opposite was true for that of the M2.
And so there is a picture that is emerging,
and I will tell those who are not familiar in this area
that it does challenge the current dogma in some way,
in which, we're seeing this shift
and that fibroblasts to be a bigger player
in the tissue remodeling or the inflammation role
of tissue remodeling, but more importantly
that the CXCR3, CXCL10 signaling access is a key modulator
that is modulating this particular feedback.
So last, in the last few minutes, I wanna,
move forward and just kind of briefly tell you
about how we take this information
even though it was really condensed and generalized
for the purpose of this presentation,
but how we take this information
and move it into a therapeutic.
So disease relevant chemokines have long been established
as disease relevant, their biomarkers, as I mentioned
and they are multifactorial and Genesis inflammation
tissue remodeling play a major role in there.
And then they're also are small,
and so delivery and synthesis are key.
So they don't necessarily they make a great drug target
or therapeutic potential because of their small size
and ability to not necessarily initiate
a strong immune response.
We have established several different chemokine technologies
and some have been, where we've developed
chemokine cocktails to allow them to work in synergy.
But I want to focus on both the remainder of the talk on,
in this particular chemokine which is more of a single use
that we've developed.
So how do you develop these, right?
So I mentioned that the same chemokine CXCL10
can actually modulate multiple cell types,
but also in different manners.
And where, how do you develop a targeted therapeutic
to actually meet the needs
of the molecular process of interest?
And so this is when we begin to look at
the structure of the chemokine
and this biological complexity
and begin to really try to fragment and dissect
potential fragments that are specific
for the induction of a particular process.
And so I don't do that.
That's not my area
but I work with a great team of biochemists.
And to date we've developed over in patents,
over 40 different chemokine targets
some agonists and antagonists.
And what I'm showing you here are those
that we've developed that are agonist and antagonist
to the CXCR3 or CXCL10 signaling access.
And so for CXCL10, for simplicity purposes,
what we found was it really was the chemokines terminal,
the N-terminus of it was the anti region
that was the area that induce the inhibition
of grow factor migration that we saw
in induce migration that we saw in the fibroblasts
and epidemial cells for that matter.
And so one of our first peptides that we developed
was a CXCL10 which is called CXCL10P.
We've also done additional fragments and found
anti pro-inflammatory portions,
and have developed those as well.
The targets that we have tested thus far
are myocardial infarction.
As I mentioned, the in-stage heart failure
which is due to fibrosis.
And so we've targeted that, we've also done targets and have
licensed this to, with a pharmaceutical company
to target IPF.
So that's now being used.
We are dually targeting two pathways, both the TGF beta
and the angiogenesis with a peptide.
And definitely we have looked at the mechanisms
in which we are being a developer
or the understanding of how COVID-19
or the SARS virus is manifesting.
And we looked at the cytokine storm.
And in fact, we found that there is these
convergent pathways that meet because the end result
of that cytokine storm is in many cases
fibrosis or a fibrotic co-morbidity as a particular organ.
And we've developed potential targets for that
that are now ongoing and will be tested very soon
in a few viral models.
So just so I have time for a few questions,
I just want to say the current thoughts of where we are now,
chemokines are important.
We're not alone, in thinking that we have
put at the forefront the investigation of CXCL10
as a potential target that remodeling, crosstalk
between the key cell types that are involved
in tissue repair.
We have learned, ways to develop these fibromatic
targeted therapies in development of peptides,
but we still have a long way to go
because even developing these, and it's really interesting
that our SARS, COVID indication really hits home
and where the potential of this could go
but it also lets us know,
other mechanisms that need to be investigated
but really how we can simultaneously modulate
to potential conversion pathways
in the treatment and that of,
those of the inflammatory and fibrotic mechanisms.
So just so I have time for questions
I've kind of already gone over the impact.
I don't want to reiterate that, but we do think
that the continued investigation of this work will allow,
hopefully allow us to translate this
into targeted individualized approaches,
using the understanding of chemokine biology
and peptide synthesis.
And so this is just my, the group that I've worked with,
I have fabulous collaborators.
I actually just talk about this.
Most of the brain power and the think tank
comes from the group that you see here.
And they have really been amazing
and across the country,
and I think all projects go much better
and smoother when you have a great team
that you're working with, experts in the field.
So with that, I will entertain any questions
- Dr. Yates.
This is Nelson ScottGale.
Thank you very much for your talk.
And I wanted to start off
with sort of a general question.
What are treatments that patients can do
to promote normal healing in fibrosis and also
are there any things that people can do
to change their chemokine secretions?
- (laughs) Well, that's the first time
anyone's ever asked me that, like, how do you change
your chemokine in patients?
I have to say that I have to really investigate in that.
I don't know what you could do holistically
to change your chemokine.
Now I can say scientifically how we can reduce inflammation.
We know different ways to do that.
We know different ways to promote healing.
And there are various,
I don't want to promote
any one over the other, but there are various molecules
that we know, vitamin D is one
that initially comes to mind
that plays a major role in both inflammation,
as well as fibrosis.
And we know that deficiency in this can cause huge
risk factors, increased risk factors for various diseases
that of diabetes, as well as COVID-19 and fibrosis.
So that part of your question, I would say,
we have some understanding how we can reduce inflammation,
but I don't think we're there yet,
provide a cocktail and say," hey, go home and drink this
and you'll be good."
Because there are underlying factors here,
because fibrosis, most fibroid
disease is a co-morbidity
and there's another source, whether it's from diabetes
heart attack, autoimmune disease.
And so that, I think we'll have to be this force
of the treatment if you want to do it holistically.
- Okay Yates, thanks for a very informative talk.
I have a question for you now,
what part of the process is abnormal
when healing tissues turn into bone?
- When healing, say that again.
- What part of the process is abnormal
when healing tissues turn into bone?
- Well, so there, if it could go awry at different stages.
And so when, if we kind of go back
to one of my initial slides, I can think of better.
Okay. Maybe not.
Yeah. So one of the earlier slides, you have this,
this inflammation and the proliferative phase, right?
And they do overlap.
As I mentioned, they're not mutually exclusive.
We always show it that way
and like these really nice find neat stages
but it's much more dynamic than that.
And if you think about the diet,
the theory of dynamic reciprocity,
there are several stages in which this could go awry, right?
If you go awry at the initiation stage
between inflammation and proliferation, if that imbalance
as I mentioned of metallic proteases occurs in there
the tissue is not being de gradated.
And so now you have this increase of
and synthesis of your osteoblasts, and in the case of bone
that are producing
bone matrix,
it won't shut it off there's no degragation
of that to resolve it.
And so, that can happen at between
the inflammation proliferation phase.
But it also can happen later on
between that proliferation in remodeling.
Yeah. It is complicated.
And, but interesting dynamic.
- Dr. Yates, one last question, I think,
do you know anything about how water plays a role
in wound healing?
When I have a cut I think it always seems more healed
after I shower or swim.
- Well, I will say is water is maybe moisture.
So when I teach anatomy physiology
to first year nursing students,
I start off with this corny joke and tell them, one,
beauty really is skin deep.
Your first layer of skin is dead.
So that is true.
It is skin deep, but also listen to your mom when she says,
don't take your scab, right?
Because it's not done healing.
And so I showed a picture of but I didn't describe it
in detail, but what happens when you cut yourself, right?
You have this denuded area, that epidermal layer is now,
has to begin to migrate from the two leading edges, right?
And your neutrophils and your macrophages
are trying to ward off all, any bacterial infection
or debris that may have gotten in there kill off
given all the dead tissue.
And as they begin to do that and they die off
and create this clot, it creates the scab.
But at the same time your two leading edges
have to come back and knit for closure.
And if you pick that scab
that clot off too soon, they haven't closed yet.
And so that's why you bleed again.
Well, one of the things that we do know that promotes the
or increases the speed of that closure is moisture.
(mumbles)
- Dr. Yates, a final question before I pass you back
to your colleague, Dr. Schreiner.
Do you believe that nanotechnology, biodegradable,
nanosscaffolds and or nanofibers
hold promise for the future?
- Absolutely. And I am a little biased in that.
Our group has developed a few polymers,
biodegradable polymers that degrade
and they integrate into the tissue
and degrade within 14 days to promote healing.
And in fact, it acts as a bio responsive.
We call it a bio band-aid because it will seal the wound
but it will also respond to the tissue.
We've gone as far as,
introducing cell types of transplant into the polymer.
And this is similar use of nanotechnology
that you can use to then signal to act almost
like this artificial smart cell that can signal
to the wound and respond to the individual environment
because everyone's wound environment is different.
And so we all respond differently.
So if we can understand the mechanism
and the pathogenesis and find a way to treat
so that the treatment is by our responses,
I think we can cast a wider net
in personalizing our treatments.
So yes, the short answer is yes
I do think it holds great promise and especially
in the area of, you know,
controlled drug delivery,
therapeutic delivery, as well as precision.
- Thank you. I now invite Dr. Schreiner
to formally thank you for a wonderful talk.
- Yeah. So on behalf of the Darwin festival committee
and the bio department, thank you so much for your talk.
As an immunologist I was like,
am used to all the talking, and I'm biased.
I usually talk about the macrophage.
So now I'm gonna have to like
make sure I really emphasis the fibroblasts.
So, so thank you again
for accepting the invitation and a wonderful talk.
- Now I know, it's actually an honor and I thank you
for inviting me.
This is great and I wish the best of my,
I look forward to attending next year as a viewer.
- Thank you everyone, that concludes this morning's webinar.
We have another one at 2:00 PM
and hopefully we'll see you there. Bye-bye.
- Thank you. Bye-bye.