GRASP55 regulates pancreatic beta-cell golgi structure and function during cytokine stress
Ended Project Grant Awarded Last action
- Award ID
- F31DK139619
- Recipient
-
The University Of Iowa UEI Z1H9VJS8NG16
- Awarding agency
-
National Institute of Diabetes and Digestive and Kidney Diseases
National Institutes of Health, Department of Health and Human Services
- Obligated
- $201,122
Award facts
- Assistance listing
- 93.847 Diabetes, Digestive, and Kidney Diseases Extramural Research
- Completion date
- Place of performance
- Iowa City, IA 52242, USA
Award details come from USAspending.gov.
Description
- Abstract
- Type 1 diabetes (T1D) results from autoimmune-mediated destruction of pancreatic SS-cells. Currently, no long- term treatments have been successful in preventing disease, and SS-cell contribution to early pathology is poorly understood. Early defects in SS-cell secretory function, such as MIS-trafficking of secretory proteins, are evident prior to symptomatic onset. These defects are suggested to play a role in early disease progression, possibly by neoantigen formation, yet underlying mechanisms are poorly understood. Our recent work demonstrates that proinflammatory cytokines, interleukin-1SS (IL-1SS), tumor necrosis factor-a (TNF-a), and interferon- (IFN-), substantially disrupt SS-cell golgi structure and function, which may explain early defects in SS-cell secretory function. The purpose of this proposal is to investigate how cytokine exposure drives alterations to golgi structure, and the implications this has on golgi functions. To this point, we demonstrate treatment with a chemical no donor can recapitulate altered SS-cell golgi structure and function. Our preliminary data further demonstrates knockdown (KD) of GRASP55, a key golgi structural protein, can substantially block golgi fragmentation during cytokine stress, which may be regulated via post-translational modification. Our central hypothesis is that proinflammatory cytokines drive no-dependent, GRASP55- mediated golgi remodeling, leading to dysfunctional protein sorting and glycosylation. We will test this hypothesis through two aims. Aim 1) will investigate the role of inos and no in altered golgi structure and cell-surface glycosylation through genetic and pharmacological models of inos inhibition, as well as flow cytometry to measure cell surface glycosylation. Aim 2) will investigate PTM regulation of GRASP55 in modulation of golgi structure and improper secretion of ctsd through GRASP55 KD models and expression of PTM-mutants in a GRASP55 knockout (KO) cell line. Pharmacological inhibition of golgi export will also be used to investigate how GRASP55-dependent golgi remodeling drives improper ctsd secretion. This proposed work will advance understanding of how proinflammatory cytokines affect SS-cell golgi structure and function, providing novel insight to SS-cell contributions to disease pathology early in T1D and potential targets for new therapeutics.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | -$2,639 | |
| Amendment | -$18,482 | |
| Amendment | -$18,482 | |
| Amendment | $564 | |
| Amendment | $34,138 | |
| Amendment | $34,138 | |
| Amendment | $1,280 | |
| Amendment | $1,280 | |
| Amendment | $1,280 | |
| Amendment | $33,609 | |
| Amendment | $0 | |
| Amendment | $33,609 | |
| Amendment | $0 | |
| Amendment | $33,609 | |
| Amendment | $0 | |
| Amendment | $33,609 | |
| Amendment | $33,609 | |
| Original award | $0 |
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Quick answers
Who received award F31DK139619?
F31DK139619 was awarded to The University Of Iowa by National Institute of Diabetes and Digestive and Kidney Diseases (National Institutes of Health) on August 16, 2024.
How much is award F31DK139619 worth?
$201,122 has been obligated on F31DK139619.
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