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Forced Activation of ATF6 Drives Pancreatic Beta Cell Dysfunction

Award Number: F31DK136225
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 03/18/2024
PERIOD OF PERFORMANCE END DATE: 03/17/2027

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Forced Activation of ATF6 Drives Pancreatic Beta Cell Dysfunction - Project Summary Pancreatic beta cells (β-cells) produce and secrete insulin in response to acute elevations in blood glucose. Diminished β-cell insulin production and secretion deregulate whole-body glucose homeostasis and are hallmarks of Type 2 Diabetes (T2D). Endoplasmic Reticulum (ER) stress and Unfolded Protein Response (UPR) activation are required steps in β-cell dysfunction. Activating Transcription Factor 6 alpha (ATF6α) is a UPR-effector protein that helps increase cellular tolerance to stress by inducing expression of genes involved in ER function. Based on extensive literature documenting the beneficial role of ATF6α, we hypothesized in vivo β-cell ATF6α activation would protect mice against diabetes. Using destabilized domain technology provided by Luke Wiseman’s lab at the Scripps Institute, the Alonso lab generated knock-in mice (C57BL/6) expressing the N-terminal fragment of human ATF6α fused to a destabilized variant of E. coli Dihydrofolate Reductase (DHFR-ATF6α). Upon constitutive expression, the destabilized DHFR domain directs DHFR-ATF6α towards proteasomal degradation until exposure to the pharmacologic chaperone, Trimethoprim (TMP), which stabilizes DHFR and turns on DHFR-ATF6α transcriptional activity. These mice allow cell-type-specific (via Cre recombinase) and temporal (via TMP) activation of ATF6α in β-cells. Surprisingly, contrary to our hypothesis in vivo β-cell DHFR-ATF6α activation caused marked glucose intolerance during an intraperitoneal (i.p.) glucose challenge. There was no loss of insulin responsiveness and β-cell mass remained intact, suggesting β-cell DHFR-ATF6α activation causes insulin insufficiency. Indeed, our preliminary data indicate loss of glucose stimulated insulin secretion in vivo and a reduced islet insulin content. Intriguingly, loss of insulin secretion preceded reduced islet insulin content, suggesting β-cell DHFR-ATF6α activation impacts these processes by distinct molecular mechanisms. In Aim1, I propose to examine the impact of in vivo β-cell DHFR-ATF6α activation on insulin production; specifically, proinsulin production, proinsulin processing, and insulin granule maturation using transmission electron microscopy. In Aim 2, I propose to examine the impact of in vivo β-cell DHFR-ATF6α activation on the insulin secretion pathway; specifically, glucose uptake, glucose metabolism, ATP production, cAMP signaling, ATP-sensitive potassium channel closure, calcium induced insulin release, and cortical actin remodeling, using the gold- standard islet perifusion assay. These aims will contribute valuable knowledge for developing therapies that help preserve and/or rescue β-cell function in T2D. ATF6α is a key component of the chronic stress response that is thought to contribute to β-cell dysfunction. Understanding the impact of continuous, inappropriate β- cell ATF6α signaling may be useful for uncovering novel molecular mechanisms that explain one part of the damaging effect of chronic stress that precedes diminished β-cell insulin production and secretion in T2D.


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 = $50,678 )
2026	2026	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	4/6/2026	NON-COMPETING CONTINUATION	$50,114
2026	2025	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	3/19/2026	NON-COMPETING CONTINUATION	$564
														Subtotal = $50,678

Issue Date FY: 2025 ( Subtotal = $48,974 )
2025	2025	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/21/2025	NON-COMPETING CONTINUATION	$48,974
														Subtotal = $48,974

Issue Date FY: 2024 ( Subtotal = $48,974 )
2024	2024	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	1	4/29/2024	NEW	$0
2024	2024	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	4/29/2024	NEW	$1,280
2024	2024	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/18/2024	NEW	$47,694
														Subtotal = $48,974

Grand Total All Awards = $148,626

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Forced Activation of ATF6 Drives Pancreatic Beta Cell Dysfunction

Award Number: F31DK136225

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 03/18/2024

PERIOD OF PERFORMANCE END DATE: 03/17/2027

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