Friday, July 4, 2025 7/4/2025

Creating a mouse and human model of a novel monogenic diabetes syndrome

Award Number: R03TR004204
ORGANIZATION: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2022
PERIOD OF PERFORMANCE END DATE: 05/31/2024

Group Awards By:

View Award Description

Creating a mouse and human model of a novel monogenic diabetes syndrome - Project Summary/Abstract One in eleven people has diabetes mellitus worldwide. Despite the development of novel therapeutics in the last decade, type 2 diabetes is progressive in most patients, showing that more effective therapies are needed. Our long-term objective is to identify genes that are important for beta cell function because these may reveal causes and therapeutic targets for diabetes. We identified a chloride channel as a potential regulator of glucose homeostasis. This channel is known to play a role in maintaining normal levels endoplasmic reticulum (ER) stress, a key process for pancreatic beta cell function and survival. A single amino acid substitution in this channel has been associated with early blindness in humans. The central focus of this grant is to model this mutation in mice and in human pluripotent stem cells to understand if and how this mutation leads to diabetes. Our central hypotheses are that this channel is required for maintenance of pancreatic beta cell ER stress and that the point mutation will result in pancreatic beta cell death from ER stress and diabetes in both mice and humans. Aim 1: Model this chloride channel mutation in mice. Mice homozygous for the mutation will be tested for diabetes. Isolated beta cells will be tested for the levels of ER chloride and the expression of markers of the unfolded protein response (UPR). We hypothesize that homozygous mice will develop diabetes, their beta cells will have lower levels of ER chloride, and markers of UPR will be upregulated. Aim 2: Create a human beta cell model of the mutation. As useful as mouse models of human disease can be, human beta cells are not exactly the same as mouse beta cells. Therefore, in this aim, we will introduce the homozygous mutation into human pluripotent stem cells and assess the ability of these cells to differentiate into enriched beta cell clusters (eBCs) in vitro. We will then assess ER stress and insulin secretion from these cells. We hypothesize that the mutation will cause decreased ER chloride, ER stress, and impaired insulin secretion. This grant will elucidate a novel role for a chloride channel in beta cell function. These studies will be significant because they may identify a novel monogenic cause of human diabetes and elucidate a novel requirement of ER chloride transport in the maintenance of ER stress.


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	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Trans-NIH Research Support	000	1	8/29/2024	NEW	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $161,500 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Trans-NIH Research Support	000	1	5/27/2022	NEW	$161,500
														Subtotal = $161,500

Grand Total All Awards = $161,500

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Creating a mouse and human model of a novel monogenic diabetes syndrome

Award Number: R03TR004204

ORGANIZATION: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2022

PERIOD OF PERFORMANCE END DATE: 05/31/2024

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer