Thursday, November 21, 2024 11/21/2024

Cytoprotection and the mechanism of action of a natural product Khellin against ER stress

Award Number: R01DK116017
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By:

View Award Abstract

Endoplasmic reticulum (ER) stress plays an important role in the pathogenesis of a growing list of human diseases, including diabetes, obesity, atherosclerosis, and neurodegenerative diseases. Chronic ER stress leads to cell dysfunction and death through the hyperactivation of the unfolded protein response (UPR), and hence has been proposed as a therapeutic target for the treatment of these diseases. However, no drugs targeting ER stress/UPR-induced cell dysfunction and death have yet been identified. Using high throughput screen technology, we have identified a natural product, a furanochromone derivative, as a molecule of cytoprotection against ER stress. Our preliminary studies revealed that (a) in cell-based assays, the furanochromone derivative protects β cells against ER stress-, glucotoxicity-, and lipotoxicity-induced dysfunction and death, (b) the furanochromone ameliorates hyperglycemia and protects the function and survival of β cells in streptozotocin-induced diabetic animals, and (c) the furanochromone also protects other cell types against ER stress. These studies revealed for the first time that this natural product exhibits cytoprotection against ER stress. Our pilot studies further indicate that the furanochromone derivative selectively inhibits the ER stress-induced activation of one of three unfolded protein response pathways, IRE1α pathway, with no effect on the other two pathways: PERK and ATF6. These findings led to our central hypothesis that this compound inhibits ER stress-induced IRE1α hyperactivation to confer cytoprotection. In this grant, we propose three aims to test this hypothesis. In aim 1, we will determine the mechanism of action of this compound on IRE1α inhibition. We will use biochemical assays to determine the effects of the furanochromone derivative on IRE1a kinase and RNase activities and its phosphorylation and dimeric/oligomeric statuses. In aim 2, we will determine whether the compound confers cytoprotective activity by inhibiting IRE1α. These studies will establish its inhibition on IRE1α activation as the molecular mechanism of the compound’s cytoprotection. Finally, we will determine therapeutic potential of the compound in well-established ER stress-related animal models: two diabetes models of progressive β cell loss (Akita mice and db/db mice). Together, this work will reveal not only a novel cytoprotective activity of the natural product against ER stress but also elucidate its inhibition of IRE1α activity as the molecular mechanism of action underlying its cytoprotection, thus establishing the foundation for the clinical development of the furanochromone derivatives as novel cytoprotective drugs for ER stress-related diseases.


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: 2025 ( Subtotal = -$7 )
2025	2021	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	10/16/2024	NON-COMPETING CONTINUATION	-$5
2025	2021	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	10/16/2024	SUPPLEMENT FOR EXPANSION	-$2
														Subtotal = -$7

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	6/2/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $507,500 )
2021	2021	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	2/2/2021	SUPPLEMENT FOR EXPANSION	$145,000
2021	2021	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	4/27/2021	NON-COMPETING CONTINUATION	$362,500
														Subtotal = $507,500

Issue Date FY: 2020 ( Subtotal = $362,500 )
2020	2020	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	5/21/2020	NON-COMPETING CONTINUATION	$362,500
														Subtotal = $362,500

Issue Date FY: 2019 ( Subtotal = $362,500 )
2019	2019	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	7/8/2019	NON-COMPETING CONTINUATION	$362,500
														Subtotal = $362,500

Issue Date FY: 2018 ( Subtotal = $362,500 )
2018	2018	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/23/2018	NEW	$362,500
														Subtotal = $362,500

Grand Total All Awards = $1,594,993

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Cytoprotection and the mechanism of action of a natural product Khellin against ER stress

Award Number: R01DK116017

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer