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

Targeting ChREBPbeta to Protect beta-Cells from Metabolic and Inflammatory Stress in Type 1 Diabetes

Award Number: R03DK147337
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/07/2026
PERIOD OF PERFORMANCE END DATE: 02/28/2028

Group Awards By:

View Award Description

Targeting ChREBPbeta to Protect beta-Cells from Metabolic and Inflammatory Stress in Type 1 Diabetes - Project Summary / Abstract Type 1 Diabetes (T1D) results from progressive destruction of pancreatic β-cells driven by autoimmune attack and intrinsic stress. While much attention has focused on immune-mediated mechanisms, the contribution of β- cell–intrinsic stress pathways to disease progression remains incompletely understood. Emerging evidence implicates ChREBPβ (Carbohydrate-Responsive Element-Binding Protein β), a stress-inducible transcription factor, as a central integrator of metabolic and inflammatory signals that impair β-cell identity and survival. Although ChREBP has been studied in the context of glucose metabolism and Type 2 Diabetes, its pathological role in T1D remains unexplored. Our preliminary data demonstrate that ChREBP and its target genes are upregulated in β-cells from autoantibody-positive (AAb+) and T1D donors, as well as in NOD mice, suggesting early activation in disease pathogenesis. ChREBPβ overexpression induces apoptosis, oxidative stress, and β-cell dedifferentiation. We also developed a novel small molecule, Compound 43, which functions as a “molecular glue” that stabilizes the ChREBPα–14-3-3 interaction, thereby suppressing ChREBPβ expression and protecting β-cells from stress- induced damage, and we demonstrate here that this stabilizer is able to protect human β-cell identity and function under cytokine-induced toxicity. This proposal aims to define the contribution of ChREBPβ to β-cell dysfunction in T1D and evaluate the therapeutic potential of Compound 43 in mitigating this process. In Aim 1, we will characterize the impact of ChREBPβ activation on β-cell stress and survival under inflammatory and ER stress conditions using human islets. We will assess gene expression, apoptosis, UPR activation, and lipid metabolism using transcriptomic and lipidomic profiling. In Aim 2, we will test whether Compound 43 can protect human islets and stem cell– derived β-cells from cytokine- and ER stress–induced dysfunction, using functional, metabolic, and transcriptomic readouts. This study will establish ChREBPβ as a previously unrecognized contributor to early β-cell failure in T1D and provide preclinical validation for a new pharmacologic approach that targets β-cell resilience, rather than immune modulation. These findings will offer a new conceptual and therapeutic framework for preserving β-cell function in the earliest stages of T1D, directly aligning with the mission of the Human Islet Research Network (HIRN) to understand and prevent β-cell failure.


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 = $168,000 )
2026	2026	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	5/11/2026	NEW	$168,000
														Subtotal = $168,000

Grand Total All Awards = $168,000

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Targeting ChREBPbeta to Protect beta-Cells from Metabolic and Inflammatory Stress in Type 1 Diabetes

Award Number: R03DK147337

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/07/2026

PERIOD OF PERFORMANCE END DATE: 02/28/2028

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer