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Molecular function of extracellular vimentin in regulating the response to lens wounding

Award Number: R01EY035771
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2029

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Molecular function of extracellular vimentin in regulating the response to lens wounding - The vimentin intermediate filament cytoskeleton can quickly sense and respond to stress in the environment, and under certain conditions become altered through post-translational modifications (PTMs) to alter its function and disassemble into soluble oligomers for extracellular release. Extracellular vimentin (eVim) has emerged as a regulator of both physiological and pathological processes, however we lack an in-depth understanding about the molecular mechanisms that regulate eVim function. Using an ex vivo post-cataract surgery model that recapitulates the major features of the lens fibrotic disease, posterior capsule opacification, our studies revealed a role for extracellular, cell-surface vimentin in promoting wound healing and fibrosis. In response to cataract surgery wounding, eVim became released into the extracellular environment, bound to the cell-surface of myofibroblast progenitor cells, linked to causing fibrosis and promoted a fibrotic response to lens injury. The objective of this proposal is to decipher the molecular mechanisms by which eVim drives a pathological fibrotic outcome to lens injury. The central hypothesis is that lens wounding stimulates alterations to the cellular environment leading to the activation of factors that cause changes in intracellular vimentin leading to the release of eVim into the extracellular space, and in the process vimentin has acquired a distinct structural form and molecular characteristics that shape eVim pro-fibrotic function, including the ability of eVim to bind to the cell surface of myofibroblast progenitor cells and signal a pathological outcome to lens injury. The rationale fundamental to this proposal is that completion of these studies will provide important new insight into the molecular regulation of eVim function in driving fibrosis that can be applied to understanding eVim function in other pathogenic processes. The proposed work will also identify key aspects of eVim regulation that may be targeted to prevent a fibrotic outcome to lens injury. The central hypothesis will be tested in the following three specific Aims: 1) Investigate mechanisms mediating vimentin release into the extracellular space and cell- surface binding post-lens wounding, 2) Investigate the mechanisms by which extracellular vimentin signals fibrosis in the lens and 3) Investigate the state of extracellular vimentin linked to driving lens fibrosis post- injury. We will pursue these aims using an innovative combination of molecular and biochemical techniques, including vimentin-linked polyacrylamide gels, a novel tool developed to study how eVim interacts with the surface of cells. The proposed research is significant, because there is a lack of comprehensive understanding about the conditions that regulate vimentin release by cells, binding of eVim to the surface of cells, and the eVim-dependent signaling intermediaries that promote fibrosis. It is also significant because the specific oligomeric form(s) and modifications that eVim adopts to modulate its function to drive lens fibrosis are elusive. The expected outcome of this work is to provide new insight into the molecular details regarding how eVim function in wound healing becomes altered to induce a fibrotic outcome to lens injury.


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: 2026 ( Subtotal = $450,118 )
2026	2026	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Vision Research	000	3	5/7/2026	NON-COMPETING CONTINUATION	$450,118
														Subtotal = $450,118

Issue Date FY: 2025 ( Subtotal = $451,480 )
2025	2025	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Vision Research	000	2	4/11/2025	NON-COMPETING CONTINUATION	$451,480
														Subtotal = $451,480

Issue Date FY: 2024 ( Subtotal = $480,805 )
2024	2024	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Vision Research	000	1	2/29/2024	NEW	$480,805
														Subtotal = $480,805

Grand Total All Awards = $1,382,403

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Molecular function of extracellular vimentin in regulating the response to lens wounding

Award Number: R01EY035771

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2029

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