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Principal Investigator: Yiqin Du
Organization: UNIVERSITY OF SOUTH FLORIDA
Fiscal Year: 2024
Award: $456,500
Funding agency: National Eye Institute
Project Summary
Glaucoma is a leading cause of irreversible blindness throughout the world and the second leading cause of
blindness overall in the USA. Elevated intraocular pressure (IOP) and aging are the most important risk factors
for most forms of glaucoma. IOP level is highly dependent on the rate at which the aqueous humor is filtered
through the conventional outflow pathway containing the trabecular meshwork (TM). Reduced cellularity within
the TM and abnormal extracellular matrix (ECM) turnover occur in glaucomatous conditions and correlate with
increased outflow resistance, elevated IOP, and subsequent vision loss. The goal of this project is to define the
mechanisms of stem cell homing and engrafting to the TM tissue, activating regeneration of the TM tissue, and
hence restoring outflow facility, reducing IOP, and preventing vision loss. In our previous funding period, we
have identified the mechanisms of stem cell homing and integration are partially associated with CXCR4/SDF1
chemokine pair and α5β1 integrin. We have also confirmed that TM stem cells (TMSCs), after intracamerally
injection, can regenerate the TM tissue, reduce IOP, and preserve the retinal ganglion cell function in a mouse
glaucoma model. This project is designed to test specific hypotheses about the mechanisms by which human
TMSCs remodel the pathological TM tissue and restore the TM function. Specific Aim 1 tests the hypothesis
that TMSCs and differentiated TM cells remodel the abnormal TM ECM via the COX2/PGE2/MMP pathway.
We will utilize myocilin mutant TM cells and dexamethasone-treated TM cells as well as a mouse glaucoma
model with myocilin mutation to test how TMSCs promote the ECM turnover and modify the TM segmental
outflow pattern. Specific Aim 2 tests the hypothesis that transplanted TMSCs can promote endogenous
TMSC activation, migration, and function via the SOX21/WNT signaling. We will unveil if the endogenous
TMSCs are viable with a reduced number in aged and glaucomatous TM tissue in human and in mice and
uncover how TMSCs awake endogenous TMSCs via SOX21/WNT signaling. The scientific impact of this study
will be the elucidation of the cellular and molecular mechanisms of TM regeneration potential by stem cells.
The results may also directly lead to the design of stem cell-based therapies or adjunctive treatments that
prevent blindness from glaucoma clinically.
Terms: <Address><Aging><Aqueous Humor><Autoregulation><Blindness><Body Tissues><COX-2><COX2><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><CXC-R4><CXCL12><CXCL12 gene><CXCL12 protein><CXCR-4><CXCR4><CXCR4 gene><Cas nuclease technology><Cell Body><Cell Function><Cell Physiology><Cell Process><Cell Survival><Cell Viability><Cell-Extracellular Matrix><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cellularity><Chemokine (C-X-C Motif) Ligand 12><Chemotactic Cytokines><Clinical><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Cornea><Cranial Nerve II><D2S201E><Data><Deposit><Deposition><Dexamethasone><Dinoprostone><Drugs><ECM><Engraftment><Extracellular Matrix><FB22><Foundations><Funding><Genetic Alteration><Genetic Change><Genetic defect><Glaucoma><Goals><HM89><HSY3RR><Home><Homeostasis><Homing><Homologous Chemotactic Cytokines><Human><Impairment><In Vitro><Injections><Integrin alpha-5 beta-1><Integrin alpha5beta1><Integrin α5β1><Intercrines><Intraocular Fluid><Intraocular Pressure><LAP3><LCR1><LESTR><Lead><MMPs><Matrix Metalloproteinases><Medication><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Murine><Mus><Mutation><NPY3R><NPYR><NPYRL><NPYY3R><Natural regeneration><Non-adherent patient><Nonadherent patient><Ocular Tension><Operative Procedures><Operative Surgical Procedures><Optic Nerve><PBSF><PGE2><PGE2 alpha><PGE2alpha><PGHS-2><PHS-2><PTGS2><PTGS2 gene><Pathologic><Pathway interactions><Patient Non Compliance><Patient Non-Adherence><Patient Nonadherence><Patient Noncompliance><Pattern><Pb element><Pharmaceutical Preparations><Phenotype><Physiologic Intraocular Pressure><Physiological Homeostasis><Platelet Glycoprotein Ic/IIa><Pre-B Cell Growth Stimulating Factor><Progenitor Cell Transplantation><Progenitor Cells><Prostaglandin E2><Prostaglandin E2 alpha><Prostaglandin E2alpha><RNA Seq><RNA sequencing><RNAseq><Regeneration><Rejuvenation><Resistance><Retinal Ganglion Cells><Risk Factors><SCYB12><SDF-1><SDF-1A><SDF-1B><SDF-1alpha><SDF1><SDF1A><SDF1B><SIS cytokines><SOX21><SOX21 gene><SOX25><SRY-Box 21><SRY-Related HMG-Box Gene 21><Sdf1 protein><Second Cranial Nerve><Site><Solid><Source><Stem Cell Transplantation><Stem Cell like><Stem cell transplant><Stromal Cell-Derived Factor 1><Subcellular Process><Surgical><Surgical Interventions><Surgical Procedure><TLSF-A><TLSF-B><TPAR1><Testing><Therapeutic><Tissues><Trabecular Meshwork><Trabecular meshwork structure><Transgenes><Transplantation><Treatment Efficacy><VLA-5><VLA-5 Receptors><WNT Signaling Pathway><WNT signaling><Work><adipose derived stem cell><adipose progenitor><adipose stem cell><aged><aqueous><awake><chemoattractant cytokine><chemokine><clinical applicability><clinical application><clinical translation><clinically translatable><corneal><design><designing><drug/agent><effective therapy><effective treatment><endogenous stem cells><experiment><experimental research><experimental study><experiments><genome mutation><glaucomatous><hCOX-2><hIRH><heavy metal Pb><heavy metal lead><homes><in vivo><in vivo Model><inhibitor><intervention efficacy><intra-ocular pressure><laser photocoagulation><life span><lifespan><migration><mouse genetics><mutant><myocilin><nerve damage><pathway><preservation><prevent><preventing><progenitor cell based therapy><progenitor cell proliferation><progenitor cell regeneration><progenitor cell self renewal><progenitor cell therapy><progenitor cell treatment><progenitor proliferation><progenitor regeneration><progenitor self renewal><progenitor therapy><progenitor transplantation><progenitor treatment><regenerate><regeneration potential><regenerative potential><repair><repaired><resistant><restoration><retinal ganglion><self-renew><self-renewal><side effect><stem and progenitor cell proliferation><stem and progenitor cell regeneration><stem and progenitor cell self renewal><stem and progenitor cell therapy><stem and progenitor cell transplantations><stem cell based therapy><stem cell characteristics><stem cell mediated therapy><stem cell proliferation><stem cell regeneration><stem cell self renewal><stem cell therapeutics><stem cell therapy><stem cell treatment><stem cell-based therapeutic><stem cell-based treatment><stem cells><stemness><stromal cell-derived factor-1alpha><stromal progenitor><stromal stem cell><surgery><therapeutic efficacy><therapy efficacy><transcriptome sequencing><transcriptomic sequencing><transgene><transplant><vision loss><visual loss>