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Trabecular Meshwork Cytoskeletal Signaling-Regulation of Aqueous Humor Outflow

Award Number: R01EY018590
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2008
PERIOD OF PERFORMANCE END DATE: 01/31/2024

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Trabecular Meshwork Cytoskeletal Signaling-Regulation of Aqueous Humor Outflow - PROJECT SUMMARY Dysregulated homeostatic mechanisms that lead to an increased resistance to aqueous humor (AH) outflow through the trabecular pathway constitute the main cause for ocular hypertension (OHT), a key risk factor for an irreversible blinding disease, glaucoma. The extracellular matrix (ECM) is well-recognized to play a crucial role in modulation of AH outflow and intraocular pressure (IOP) via regulating the contractile, adhesive, fibrogenic and permeability characteristics of the trabecular outflow pathway cells. There still exists a fundamental gap in our understanding however, of how post-translational modifications of ECM proteins and ECM degrading enzymes might influence trabecular meshwork (TM) cell behavior, AH outflow and IOP. The broad objective of this proposal is to examine protein phosphorylation of ECM components and matrix metalloproteinases (MMPs), and determine how this modification modulates AH outflow and IOP, with the goal of uncovering novel insights into OHT etiology and developing efficacious strategies for glaucoma treatment. The scientific premise is that protein tyrosine kinases and phosphatases in the AH secreted by TM and other cell types play a vital role in homeostasis of AH outflow and IOP by modifying protein tyr-phosphorylation status of ECM and MMPs that in turn influences TM cell contractile, adhesive, fibrogenic and barrier activities. We hypothesize that deregulation of tyr-phosphorylation of ECM proteins and MMPs resulting from alterations in the levels of secretory tyrosine kinases and phosphatases may be a key etiological contribution to impaired AH outflow and elevated IOP in glaucoma. In support of this novel and paradigm shifting hypothesis, our recent studies detected vertebrate lonesome kinase (VLK) and phosphatase and tensin homolog (PTEN) proteins in human AH samples, and demonstrated that HTM cells secrete both enzymes. Significantly, VLK was shown to regulate ECM tyr-phosphorylation, and contractile and adhesive activities of TM cells, and induced by TGF-β2 and dexamethasone in human TM cells, both of which are known to induce OHT. Based on these promising and novel preliminary results, we have outlined three specific aims in this competing proposal, focused on mechanistic investigations into the role(s) of VLK in: 1) regulation of intracellular signaling pathways controlling TM cell contractile, cell-ECM & cell-cell adhesive, fibrogenic and permeability characteristics, 2) Tyr-phosphorylation of TM cell ECM and MMPs, ECM organization and TM cell stiffness, and 3) AH outflow and IOP, using human TM cells, human donor eyes and rats. These studies will utilize gene targeting, proteomics, biophysical, histological and physiological approaches, and include an assessment of changes in levels of VLK and PTEN in AH samples from glaucoma versus non-glaucoma (cataract) patients. Completion of the novel studies proposed in this application is expected to uncover new understanding on the role of tyr-phosphorylation of ECM proteins and MMPs in AH outflow and OHT etiology via altered outside-in signaling, and to identify new and efficacious treatment strategies for lowering IOP in glaucoma patients.


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 = $0 )
2024	2022	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Vision Research	000	13	8/15/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $390,425 )
2022	2022	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Vision Research	000	13	2/3/2022	NON-COMPETING CONTINUATION	$390,425
														Subtotal = $390,425

Issue Date FY: 2021 ( Subtotal = $390,425 )
2021	2021	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Vision Research	001	12	2/22/2021	NON-COMPETING CONTINUATION	$28,175
2021	2021	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Vision Research	000	12	2/1/2021	NON-COMPETING CONTINUATION	$362,250
														Subtotal = $390,425

Issue Date FY: 2020 ( Subtotal = $402,500 )
2020	2020	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Vision Research	000	11	1/15/2020	NON-COMPETING CONTINUATION	$402,500
														Subtotal = $402,500

Issue Date FY: 2019 ( Subtotal = $401,458 )
2019	2019	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Vision Research	001	10	1/31/2019	COMPETING CONTINUATION	$401,458
2019	2017	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Vision Research	002	9	6/25/2019	NON-COMPETING CONTINUATION	$0
2019	2017	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Vision Research	000	9	1/28/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $401,458

Issue Date FY: 2017 ( Subtotal = $392,500 )
2017	2017	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Vision Research	000	9	4/14/2017	NON-COMPETING CONTINUATION	$353,250
2017	2017	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Vision Research	001	9	7/24/2017	NON-COMPETING CONTINUATION	$39,250
														Subtotal = $392,500

Issue Date FY: 2016 ( Subtotal = $392,500 )
2016	2016	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Vision Research	000	8	4/25/2016	EXTENSION WITH OR WITHOUT FUNDS	$392,500
														Subtotal = $392,500

Issue Date FY: 2015 ( Subtotal = $384,650 )
2015	2015	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Vision Research	000	7	4/3/2015	NON-COMPETING CONTINUATION	$384,650
														Subtotal = $384,650

Issue Date FY: 2014 ( Subtotal = $384,650 )
2014	2014	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Vision Research	000	6	4/4/2014	NON-COMPETING CONTINUATION	$384,650
														Subtotal = $384,650

Issue Date FY: 2013 ( Subtotal = $392,500 )
2013	2013	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Vision Research	002	5	5/1/2013	COMPETING CONTINUATION	$392,500
2013	2011	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Vision Research	000	4	1/14/2013	NON-COMPETING CONTINUATION	$0
2013	2011	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Vision Research	001	4	4/26/2013	NON-COMPETING CONTINUATION	$0
														Subtotal = $392,500

Issue Date FY: 2011 ( Subtotal = $374,400 )
2011	2011	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Vision Research	001	4	5/26/2011	NON-COMPETING CONTINUATION	$23,400
2011	2011	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Vision Research	000	4	12/9/2010	NON-COMPETING CONTINUATION	$351,000
2011	2009	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Trans-NIH Recovery Act Research Support	002	2	8/4/2011	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $374,400

Issue Date FY: 2010 ( Subtotal = $386,100 )
2010	2010	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Vision Research	001	3	1/14/2010	NON-COMPETING CONTINUATION	$35,100
2010	2010	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Vision Research	000	3	12/15/2009	NON-COMPETING CONTINUATION	$351,000
														Subtotal = $386,100

Issue Date FY: 2009 ( Subtotal = $875,096 )
2009	2009	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Vision Research	001	2	4/29/2009	NON-COMPETING CONTINUATION	$39,000
2009	2009	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Vision Research	000	2	12/19/2008	NON-COMPETING CONTINUATION	$351,000
2009	2009	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Trans-NIH Recovery Act Research Support	002	2	7/31/2009	SUPPLEMENT FOR EXPANSION	$485,096
														Subtotal = $875,096

Issue Date FY: 2008 ( Subtotal = $390,000 )
2008	2008	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Vision Research	000	1	12/17/2007	NEW	$390,000
														Subtotal = $390,000

Grand Total All Awards = $5,557,204

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Trabecular Meshwork Cytoskeletal Signaling-Regulation of Aqueous Humor Outflow

Award Number: R01EY018590

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2008

PERIOD OF PERFORMANCE END DATE: 01/31/2024

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