Forced activation of ATF6 drives pancreatic beta cell dysfunction
Active Project Grant Awarded Last action
- Award ID
- F31DK136225
- Recipient
-
Weill Medical College Of Cornell University UEI YNT8TCJH8FQ8
- Awarding agency
-
National Institute of Diabetes and Digestive and Kidney Diseases
National Institutes of Health, Department of Health and Human Services
- Obligated
- $245,858
Award facts
- Assistance listing
- 93.847 Diabetes, Digestive, and Kidney Diseases Extramural Research
- Completion date 84% complete
- Place of performance
- New York, NY 10065, USA
Award details come from USAspending.gov.
Description
- Abstract
- Pancreatic beta cells (SS-cells) produce and secrete insulin in response to acute elevations in blood glucose. Diminished SS-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 SS-cell dysfunction. Activating transcription factor 6 alpha (ATF6A) 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 ATF6A, we hypothesized in vivo SS-cell ATF6A 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 ATF6A fused to a destabilized variant of e. Coli dihydrofolate reductase (dhfr-ATF6A). Upon constitutive expression, the destabilized dhfr domain directs dhfr-ATF6A towards proteasomal degradation until exposure to the pharmacologic chaperone, trimethoprim (TMP), which stabilizes dhfr and turns on dhfr-ATF6A transcriptional activity. These mice allow cell-type-specific (via CRE recombinase) and temporal (via TMP) activation of ATF6A in SS-cells. Surprisingly, contrary to our hypothesis in vivo SS-cell dhfr-ATF6A activation caused marked glucose intolerance during an intraperitoneal (I.P.) glucose challenge. There was no loss of insulin responsiveness and SS-cell mass remained intact, suggesting SS-cell dhfr-ATF6A 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 SS-cell dhfr-ATF6A activation impacts these processes by distinct molecular mechanisms. In AIM1, i propose to examine the impact of in vivo SS-cell dhfr-ATF6A 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 SS-cell dhfr-ATF6A 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 SS-cell function in T2D. ATF6A is a key component of the chronic stress response that is thought to contribute to SS-cell dysfunction. Understanding the impact of continuous, inappropriate SS- cell ATF6A signaling may be useful for uncovering novel molecular mechanisms that explain one part of the damaging effect of chronic stress that precedes diminished SS-cell insulin production and secretion in T2D.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $50,114 | |
| Amendment | $564 | |
| Amendment | $564 | |
| Amendment | $48,974 | |
| Amendment | $1,280 | |
| Amendment | $0 | |
| Amendment | $0 | |
| Amendment | $1,280 | |
| Amendment | $47,694 | |
| Amendment | $47,694 | |
| Original award | $47,694 |
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Quick answers
Who received award F31DK136225?
F31DK136225 was awarded to Weill Medical College Of Cornell University by National Institute of Diabetes and Digestive and Kidney Diseases (National Institutes of Health) on September 18, 2024.
How much is award F31DK136225 worth?
$245,858 has been obligated on F31DK136225.
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