Elucidating the role of the RNF20 histone modifier in pancreatic beta cell function and senescence
Ended Project Grant Awarded Last action
- Award ID
- F31DK137440
- Recipient
-
University Of Alabama At Birmingham UEI YND4PLMC9AN7
- Awarding agency
-
National Institute of Diabetes and Digestive and Kidney Diseases
National Institutes of Health, Department of Health and Human Services
- Obligated
- $126,187
Award facts
- Assistance listing
- 93.847 Diabetes, Digestive, and Kidney Diseases Extramural Research
- Completion date
- Place of performance
- Birmingham, AL 35294, USA
Award details come from USAspending.gov.
Description
- Abstract
- Diabetes is characterized by the loss of functional pancreatic SS-cell mass. With the prevalence of diabetes increasing across the globe, IT is crucial that we develop a complete understanding of the gene regulatory mechanisms governing the maintenance of insulin-producing SS-cell identity and function. In our previous work, we demonstrated that the ISL1 transcription factor and its histone-modifying CO-regulators RNF20 and RNF40 are crucial for SS-cell gene expression. Recently, we observed that in mice, SS-cell-specific loss of RNF20 (RNF20SS-cell) prompts a disruption of glucose homeostasis, loss of SS-cell identity gene expression, and an upregulation of cell cycle inhibitor mrna, P19ARF. In aging human and mouse SS-cells, cell cycle inhibitors encoded by CDKN2A, P19ARF and P16INK4A, are upregulated and impart a reduction in functional capacity known as senescence. While suppression of the age-associated upregulation in CDKN2A expression is known to reverse SS-cell senescence, the transcriptional mechanisms that repress CDKN2A in healthy SS-cells are understudied. In this proposal, i will investigate the regulatory relationship between RNF20 and CDKN2A to assess whether RNF20 mediates SS-cell senescence. My primary hypothesis is that RNF20 protects against senescence-associated loss of SS-cell functional identity through direct regulation of the CDKN2A locus. I will address this hypothesis with two aims. In aim 1, i will evaluate how the SS-cell specific loss of RNF20 affects the SS-cell cycle and the appearance of the senescence-associated secretory phenotype. I will also perform systemic senolytic treatment to determine if targeted elimination of senescent cells rescues the glucose intolerance and reduced plasma insulin levels that occur in RNF20SS-cell mice. In aim 2, i will determine whether RNF20 regulates the transcription of CDKN2A. I will perform chromatin immunoprecipitation (chip) to assess if RNF20 directly occupies the CDKN2A promoter and atac-SEQ to see if loss of RNF20 increases CDKN2A chromatin accessibility. Our results will increase understanding of the transcriptional mechanisms regulating both the maintenance of SS-cell identity and the process of SS-cell senescence. Additionally, our outcomes may be used to inform future diabetes therapies through either the incorporation of RNF20 into either SS-cell differentiation protocols or as a biomarker for SS-cell health. Furthermore, the proposed research plan provides a balanced training platform wherein i will expand both my critical thinking and technical skillset through my investigations of novel regulatory mechanisms of SS- cell homeostasis. As a trainee at the university of alabama at birmingham (UAB) and in UAB's diabetes research center, i have access to a strong community of supportive faculty members to assist in the successful completion of the proposed study. Taken together, this research and training plan is a fundamental catalyst of my trajectory toward becoming an independent research scientist.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | -$1,947 | |
| Amendment | $1,947 | |
| Amendment | -$3,531 | |
| Amendment | -$3,531 | |
| Amendment | $0 | |
| Amendment | $0 | |
| Amendment | $1,280 | |
| Amendment | $1,280 | |
| Amendment | $0 | |
| Amendment | $43,563 | |
| Amendment | $43,563 | |
| Original award | $43,563 |
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Quick answers
Who received award F31DK137440?
F31DK137440 was awarded to University Of Alabama At Birmingham by National Institute of Diabetes and Digestive and Kidney Diseases (National Institutes of Health) on September 18, 2024.
How much is award F31DK137440 worth?
$126,187 has been obligated on F31DK137440.
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