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Corneal Epithelial-Stromal Interactions During Regeneration and Fibrosis

Award Number: R01EY005665
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/1984
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Corneal Epithelial-Stromal Interactions During Regeneration and Fibrosis - SUMMARY Corneal wound healing is a complex process involving corneal epithelial cell proliferation, myofibroblast generation, and extracellular matrix (ECM) deposition. In corneal wound models, the disruption of the Bowman's layer that separates the epithelium from stroma is often observed, and this disruption may lead to a different pathological (fibrotic) state, which we propose can be mediated by the intercellular signaling between epithelial and stromal cells in part via paracrine factors. TGF-β is a pleiotropic cytokine that exists in three isoforms (TGF-β1, -β2, and -β3), which exert biological effects through signaling pathways to maintain corneal integrity and wound healing. Previously, we found that TGF-β1 is involved in corneal fibrotic wound healing by stimulating myofibroblast differentiation; whereas, TGF-β3 application after corneal wounding reversed and diminished the fibrotic response in vitro and in vivo, respectively. Despite the functional differences in TGF-β isoforms, the molecular mechanisms in dampening fibrosis remain poorly understood. Amid other paracrine factors, extracellular vesicles (EVs) are recognized as mediators for cell-cell communication. EVs can selectively engulf a part of their parental cell and become enriched in a repertoire of bioactive cargo (e.g., proteins or lipids), and offset their cargo into recipient cells by ensuing physiological changes. We have shown that corneal epithelial cell-derived EVs can trigger myofibroblast differentiation and generate an ECM microenvironment that promotes myofibroblast persistence, which is key for corneal scarring; however, the bioactive cargo driving this remains unclear. Of disease relevance, keratoconus (KCN) is of interest because it leads to corneal stromal scarring even without any acute trauma or known underlying etiology. Pathologically, KCN is similar to our wound-healing models in that the KCN corneas: 1) develop gaps in Bowman's layer that allow direct contact between epithelium and stroma; 2) have EVs present between epithelial cells and stroma; and 3) develop myofibroblast differentiation that leads to scarring under the breaks in Bowman's layer. TGF-β's role in myofibroblast differentiation and ECM remodeling suggests involvement in KCN's pathogenesis, either in a causative or secondary repair role, leading to structural changes in KCN. In this proposal, we hypothesize that loading TGF-β3 onto EVs and applying to corneal wounds will drive healing without scarring by dampening the fibrotic response and preventing the onset of scar formation; however, TGF-β1-EVs will enhance the scarring in corneal wounds. Through these experiments we will also determine bioactive cargo from KCN-epithelial cell derived EVs that is contributing to KCN corneal scarring and disease progression. Relevance to Public Health—Collectively, this proposal will provide key mechanistic insights into corneal EV biology and their corresponding cargo, as well as identify the bioactive EV cargo that could be used to predict corneal scarring in KCN patients in the future.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $616,322 )
2024	2024	SCHEPENS EYE RESEARCH INSTITUTE, INC., THE	20 STANIFORD ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	002	39	8/9/2024	NON-COMPETING CONTINUATION	$616,322
2024	2023	SCHEPENS EYE RESEARCH INSTITUTE, INC., THE	20 STANIFORD ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	001	38	8/9/2024	NON-COMPETING CONTINUATION	$0
2024	2022	SCHEPENS EYE RESEARCH INSTITUTE, INC., THE	20 STANIFORD ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	37	8/9/2024	COMPETING CONTINUATION	$0
														Subtotal = $616,322

Issue Date FY: 2023 ( Subtotal = $524,717 )
2023	2023	SCHEPENS EYE RESEARCH INSTITUTE, INC., THE	20 STANIFORD ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	002	38	8/24/2023	NON-COMPETING CONTINUATION	$524,717
2023	2022	SCHEPENS EYE RESEARCH INSTITUTE, INC., THE	20 STANIFORD ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	001	37	7/2/2023	COMPETING CONTINUATION	$44,778
2023	2021	SCHEPENS EYE RESEARCH INSTITUTE, INC., THE	20 STANIFORD ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	36	7/2/2023	NON-COMPETING CONTINUATION	-$44,778
														Subtotal = $524,717

Issue Date FY: 2022 ( Subtotal = $524,717 )
2022	2022	SCHEPENS EYE RESEARCH INSTITUTE INC	20 STANIFORD ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	001	37	8/25/2022	COMPETING CONTINUATION	$524,717
2022	2021	SCHEPENS EYE RESEARCH INSTITUTE INC	20 STANIFORD ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	36	8/19/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $524,717

Issue Date FY: 2021 ( Subtotal = $477,725 )
2021	2021	SCHEPENS EYE RESEARCH INSTITUTE, INC., THE	20 STANIFORD ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	36	4/7/2021	NON-COMPETING CONTINUATION	$477,725
														Subtotal = $477,725

Issue Date FY: 2020 ( Subtotal = $492,500 )
2020	2020	SCHEPENS EYE RESEARCH INSTITUTE, INC., THE	20 STANIFORD ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	35	3/19/2020	NON-COMPETING CONTINUATION	$492,500
														Subtotal = $492,500

Issue Date FY: 2019 ( Subtotal = $492,500 )
2019	2019	SCHEPENS EYE RESEARCH INSTITUTE, INC., THE	20 STANIFORD ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	34	3/14/2019	NON-COMPETING CONTINUATION	$492,500
														Subtotal = $492,500

Issue Date FY: 2018 ( Subtotal = $492,500 )
2018	2018	SCHEPENS EYE RESEARCH INSTITUTE, INC., THE	20 STANIFORD ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	33	2/28/2018	COMPETING CONTINUATION	$492,500
2018	2017	SCHEPENS EYE RESEARCH INSTITUTE, INC., THE	20 STANIFORD ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	001	32	5/8/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $492,500

Issue Date FY: 2017 ( Subtotal = $492,500 )
2017	2017	SCHEPENS EYE RESEARCH INSTITUTE, INC., THE	20 STANIFORD ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	32	12/15/2016	NON-COMPETING CONTINUATION	$443,250
2017	2017	SCHEPENS EYE RESEARCH INSTITUTE, INC., THE	20 STANIFORD ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	001	32	8/14/2017	NON-COMPETING CONTINUATION	$49,250
														Subtotal = $492,500

Issue Date FY: 2016 ( Subtotal = $492,500 )
2016	2016	SCHEPENS EYE RESEARCH INSTITUTE	20 STANIFORD STREET	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	31	12/3/2015	NON-COMPETING CONTINUATION	$443,250
2016	2016	SCHEPENS EYE RESEARCH INSTITUTE	20 STANIFORD STREET	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	001	31	1/29/2016	NON-COMPETING CONTINUATION	$49,250
														Subtotal = $492,500

Issue Date FY: 2015 ( Subtotal = $482,650 )
2015	2015	SCHEPENS EYE RESEARCH INSTITUTE	20 STANIFORD STREET	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	30	12/12/2014	NON-COMPETING CONTINUATION	$443,250
2015	2015	SCHEPENS EYE RESEARCH INSTITUTE	20 STANIFORD STREET	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	001	30	3/30/2015	NON-COMPETING CONTINUATION	$39,400
														Subtotal = $482,650

Issue Date FY: 2014 ( Subtotal = $492,500 )
2014	2014	SCHEPENS EYE RESEARCH INSTITUTE	20 STANIFORD STREET	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	001	29	12/25/2013	COMPETING CONTINUATION	$492,500
2014	2012	SCHEPENS EYE RESEARCH INSTITUTE	20 STANIFORD STREET	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	28	12/20/2013	COMPETING CONTINUATION	$0
														Subtotal = $492,500

Issue Date FY: 2012 ( Subtotal = $485,000 )
2012	2012	SCHEPENS EYE RESEARCH INSTITUTE	20 STANIFORD STREET	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	28	9/3/2012	COMPETING CONTINUATION	$485,000
2012	2011	SCHEPENS EYE RESEARCH INSTITUTE	20 STANIFORD STREET	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	001	27	9/3/2012	NON-COMPETING CONTINUATION	$0
														Subtotal = $485,000

Issue Date FY: 2011 ( Subtotal = $571,835 )
2011	2011	SCHEPENS EYE RESEARCH INSTITUTE	20 STANIFORD STREET	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	27	7/14/2011	NON-COMPETING CONTINUATION	$571,835
														Subtotal = $571,835

Issue Date FY: 2010 ( Subtotal = $697,114 )
2010	2010	SCHEPENS EYE RESEARCH INSTITUTE	20 STANIFORD STREET	BOSTON	MA	02114	SUFFOLK	USA	Trans-NIH Recovery Act Research Support	000	25	1/29/2010	SUPPLEMENT FOR EXPANSION	$118,804
2010	2010	SCHEPENS EYE RESEARCH INSTITUTE	20 STANIFORD STREET	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	001	26	7/15/2010	NON-COMPETING CONTINUATION	$578,310
														Subtotal = $697,114

Issue Date FY: 2009 ( Subtotal = $567,140 )
2009	2009	SCHEPENS EYE RESEARCH INSTITUTE	20 STANIFORD STREET	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	25	7/29/2009	NON-COMPETING CONTINUATION	$567,140
														Subtotal = $567,140

Issue Date FY: 2008 ( Subtotal = $889,606 )
2008	2008	SCHEPENS EYE RESEARCH INSTITUTE	20 STANIFORD STREET	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	001	24	9/18/2008	SUPPLEMENT FOR EXPANSION	$350,000
2008	2008	SCHEPENS EYE RESEARCH INSTITUTE	20 STANIFORD STREET	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	24	7/21/2008	NON-COMPETING CONTINUATION	$539,606
														Subtotal = $889,606

Issue Date FY: 2007 ( Subtotal = $540,138 )
2007	2007	SCHEPENS EYE RESEARCH INSTITUTE	20 STANIFORD STREET	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	23	8/20/2007	COMPETING CONTINUATION	$540,138
														Subtotal = $540,138

Issue Date FY: 2006 ( Subtotal = $533,134 )
2006	2006	SCHEPENS EYE RESEARCH INSTITUTE	20 STANIFORD STREET	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	22	1/20/2006	NON-COMPETING CONTINUATION	$533,134
														Subtotal = $533,134

Issue Date FY: 2005 ( Subtotal = $530,106 ) (Continued on the next page)
Grand Total All Awards = $13,917,572

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Corneal Epithelial-Stromal Interactions During Regeneration and Fibrosis

Award Number: R01EY005665

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/01/1984

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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