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The Roles of Autophagy in Limbal/Corneal Epithelia

Award Number: R01EY028560
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2018
PERIOD OF PERFORMANCE END DATE: 02/28/2029

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The Roles of Autophagy in Limbal/Corneal Epithelia - PROJECT SUMMARY/ABSTRACT The long-term goal of this project is to understand the functions of selective autophagy in corneal inflammation as well as corneal/limbal epithelial differentiation. Selective autophagy is a specialized form of autophagy and can control signaling pathways in cells by specifically degrading key components of these pathways. Even though our studies have advanced our understanding on the roles of non selective autophagy in corneal/limbal epithelia, the roles of selective autophagy in corneal inflammation and corneal/limbal epithelial differentiation remain unclear. Single-cell RNA-sequencing (scRNA-seq) methodologies enable the interrogation of relatively rare cell populations (e.g., stem and early transit amplifying (TA) cells). This technology also allows the comparison of different physiological and/or disease states. Thus, we took advantage of Beclin1+/- (Beclin1 het) mice, a well-established mouse model with compromised autophagy and conducted a scRNA-seq analysis in the ocular anterior segmental tissue from wild-type (WT) and beclin1 het mice. scRNA-seq data suggest that autophagy plays a significant role in response to corneal inflammation, epithelial differentiation, and the regulation of Notch signaling. Our preliminary data show that genetic attenuation of autophagy enhances corneal inflammation. Interestingly, TRAF2, a positive regulator of inflammation, is regulated by NDP52- mediated selective autophagy. Furthermore, we have demonstrated that attenuation of p62-mediated selective autophagy markedly increased: (i) stem/TA cell enriched human limbal epithelial cell (HLEC) differentiation; and (ii) Notch intracellular domain (Notch ICD, an active form of Notch) in HLECs in a proteosome independent way. The scRNA-seq data also suggested that Wdfy1, which is preferentially expressed in the mouse limbal epithelial basal layer, was positively regulated by autophagy. Knockdown of Wdfy1 enhanced HLEC differentiation. Therefore, we will question if: (i) NDP52-mediated selective autophagy degrades TRAF2 and consequently has an inhibitory role in the inflammatory response in both corneal epithelial cells and macrophages (Aim1); and (ii) downregulation of p62-mediated selective autophagy allows for limbal epithelial differentiation via increasing Notch ICD (active form) and thus decreasing Wdfy1 expression (Aim2). To accomplish these goals, we will capitalize on our ability to conduct gain- and loss-of-function studies of selective autophagy-related genes in submerged and 3D organotypic raft cultures of primary limbal/corneal epithelial cells as well as mice. Knowledge gained from this study will provide molecular insights into how selective autophagy regulates corneal inflammation and limbal epithelial differentiation. A better understanding of the physiological importance of selective autophagy in corneal inflammation and differentiation will translate into the development of novel therapies by targeting selective autophagy pathways for corneal diseases in which extensive inflammation and aberrant differentiation are features (e.g., chemical burns).


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 = $464,339 )
2026	2026	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Vision Research	000	8	4/1/2026	NON-COMPETING CONTINUATION	$464,339
														Subtotal = $464,339

Issue Date FY: 2025 ( Subtotal = $464,339 )
2025	2025	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Vision Research	001	7	3/13/2025	NON-COMPETING CONTINUATION	$464,339
2025	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Vision Research	000	5	11/21/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $464,339

Issue Date FY: 2024 ( Subtotal = $481,939 )
2024	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Vision Research	000	6	2/21/2024	COMPETING CONTINUATION	$481,939
2024	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Vision Research	001	5	3/8/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $481,939

Issue Date FY: 2022 ( Subtotal = $480,797 )
2022	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Vision Research	000	5	4/26/2022	NON-COMPETING CONTINUATION	$480,797
														Subtotal = $480,797

Issue Date FY: 2021 ( Subtotal = $480,801 )
2021	2021	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Vision Research	000	4	5/3/2021	NON-COMPETING CONTINUATION	$480,801
														Subtotal = $480,801

Issue Date FY: 2020 ( Subtotal = $495,671 )
2020	2020	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Vision Research	000	3	7/29/2020	NON-COMPETING CONTINUATION	$495,671
														Subtotal = $495,671

Issue Date FY: 2019 ( Subtotal = $495,671 )
2019	2019	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Vision Research	000	2	4/8/2019	NON-COMPETING CONTINUATION	$495,671
														Subtotal = $495,671

Issue Date FY: 2018 ( Subtotal = $518,671 )
2018	2018	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Vision Research	000	1	4/16/2018	NEW	$518,671
														Subtotal = $518,671

Grand Total All Awards = $3,882,228

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The Roles of Autophagy in Limbal/Corneal Epithelia

Award Number: R01EY028560

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2018

PERIOD OF PERFORMANCE END DATE: 02/28/2029

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