Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Endothelin-1 System Activation and Retinal Microvascular Dysregulation during Early Diabetes

Award Number: R01EY034145
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2027

Group Awards By:

View Award Description

Endothelin-1 System Activation and Retinal Microvascular Dysregulation during Early Diabetes - Diabetes mellitus causes microvascular complications in the retina and is a leading cause of blindness in the United States. Treatments to restore vision are limited. Reduced retinal blood flow occurs in early diabetes, suggesting that vasomotor dysregulation of retinal arterioles and/or venules leading to ischemia may contribute to later retinal damage. However, no study has examined both arteriolar and venular vasomotor function together in the retina of same diabetic subjects. Thus, a gap in knowledge is the limited understanding of mechanisms for retinal arteriolar/venular vasomotor dysregulation in early diabetes to yield treatment before overt pathology. Excessive production of vasoconstrictor and inflammatory agent endothelin-1 (ET-1) in the retina occurs in early diabetes, so in-depth insight into molecular events regulating vasomotor responses to ET-1 in health and disease has clinical implication. This proposal is based on evidence in type 1 diabetic pigs showing reduced retinal blood flow at 2-wk diabetes, along with elevated retinal lactate and diminished oscillatory potentials in the electroretinogram, indicating retinal ischemia and neural abnormality. Also, vitreous ET-1 level and retinal arteriolar endothelin- converting enzyme-1 (ECE-1) activity were elevated in diabetic pigs. Because ET-1 is derived from ECE-1 and causes vasoconstriction via Rho kinase (ROCK) signaling, activation of ECE-1/ROCK may lead to retinal vasomotor dysregulation and flow deficiency in early diabetes. Interestingly, diabetes enhances retinal venular, but not arteriolar, constriction to ET-1 by activating reverse-mode Na+-Ca2+ exchanger (NCX), possibly involving Na+-H+ exchanger-1 (NHE1) and stress kinases (p38 and JNK). Thus, the objective of this study is to unveil the sequential molecular pathways for vasomotor dysregulation of retinal arterioles and venules that promote retinal ischemia in early diabetes. The central hypothesis is that early diabetes activates microvascular ECE-1 leading to enhanced ET- 1 production, which promotes retinal arteriolar constriction via Ca2+-dependent ROCK2/JNK signaling. In early diabetes, the elevated ET-1 not only elicits retinal venular constriction via Ca2+-dependent ROCK1/JNK axis but also augments the response by further promoting Ca2+ entry through activation of the p38/NHE1/NCX axis. The cooperative promotion of arteriolar and venular constrictions to elevated ET-1 contributes to retinal ischemia and neural abnormality. Two specific aims will be pursued to support the hypothesis: (1) Determine roles of ET-1 system activation and its molecular signaling in promoting retinal arteriolar constriction and consequent retinal ischemia via Ca2+-dependent ROCK2/JNK axis in early diabetes. (2) Determine roles of ET-1 system activation and its molecular signaling to augment retinal venular constriction with consequent retinal ischemia via Ca2+- dependent ROCK1/JNK axis and activated p38/NHE1/NCX signaling pathway in early diabetes. Outcomes will advance the knowledge of diabetes-induced retinal complications and suggest effective molecular targets for improving and protecting retinal microvascular perfusion of the retina in early-stage diabetes before development of retinal structure damage.


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 = $378,750 )
2026	2026	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Vision Research	000	5	7/30/2026	NON-COMPETING CONTINUATION	$378,750
														Subtotal = $378,750

Issue Date FY: 2025 ( Subtotal = $321,938 )
2025	2025	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Vision Research	000	4	9/19/2025	NON-COMPETING CONTINUATION	$321,938
														Subtotal = $321,938

Issue Date FY: 2024 ( Subtotal = $378,750 )
2024	2024	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Vision Research	000	3	7/22/2024	NON-COMPETING CONTINUATION	$378,750
														Subtotal = $378,750

Issue Date FY: 2023 ( Subtotal = $378,750 )
2023	2023	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Vision Research	000	2	7/13/2023	NON-COMPETING CONTINUATION	$378,750
														Subtotal = $378,750

Issue Date FY: 2022 ( Subtotal = $378,750 )
2022	2022	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Vision Research	000	1	9/9/2022	NEW	$378,750
														Subtotal = $378,750

Grand Total All Awards = $1,836,938

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Endothelin-1 System Activation and Retinal Microvascular Dysregulation during Early Diabetes

Award Number: R01EY034145

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/30/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2027

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer