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Elucidating how transcription factors MAFA and MAFB and mitochondrial activity control human Î² cell identity and function

Award Number: K01DK133533
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

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Elucidating how transcription factors MAFA and MAFB and mitochondrial activity control human Î² cell identity and function - Project Summary Type 2 diabetes (T2D) can be attributed to loss of β-cell identity or de-differentiation, marked by acquisition of immature cell markers and loss of insulin expression and secretion. While the etiology of β-cell immaturity in T2D is unclear, impairments in nuclear-encoded mitochondrial gene expression and transcription factor (TF) expression occur. Additionally, defects in mitochondrial structure and function leads to impaired glucose- stimulated insulin secretion (GSIS) and have been reported in β-cells of human T2D patients. Interestingly, the transcriptional changes that occur during β-cell immaturity involve loss of the nuclear-encoded mitochondrial gene expression program. My studies will test the hypothesis that β-cell immaturity in T2D is driven by loss of mitochondrial functional gene regulation by the TFs MAF bZIP transcription factor A (MAFA) or B (MAFB). Furthermore, I predict that MAFA/MAFB are themselves targets of mito-nuclear crosstalk through a retrograde signaling cascade induced by defects in mitochondrial function. I will elucidate the contribution of MAFA and MAFB on metabolic control in human β cells through regulation of mitochondrial function (Aim 1). I will determine how loss of MAFA and/or MAFB affects mitochondrial function and β cell identity by assaying oxygen consumption and gene expression in MAFA and/or MAFB knockdown human pseudoislets and EndoC-βH3 β cell lines. Metabolomics will be performed on EndoC- βH3 β cell lines to determine how MAFA/B influences fuel utilization. My preliminary data shows that genetic loss of mitophagy (i.e., the balance of mitochondrial biogenesis and turnover) reduces β-cell maturity. This includes physiologic, metabolic, and transcriptional signatures consistent with metabolic overload, oxidative damage, and the integrated stress response (ISR). MAFA (and likely MAFB) is known to be more sensitive to oxidative stress associated with T2D β-cell dysfunction than other TFs. While nuclear expression of β-cell mitochondrial genes are well known, mitochondrial feedback to drive β-cell nuclear gene expression (retrograde signaling) has not been analyzed. I will delineate if TF levels and β-cell maturity are altered in response to mitochondrial dysfunction (Aim 2). Further, I observed that pharmacological inhibition of the ISR relieves markers of immaturity in islets of mitophagy-deficient mice. Utilizing pharmacologic tools and analysis of gene expression in human pseudoislet transplants and EndoC-βH3 cells, I will interrogate how such conditions impact human β cells. I expect that MAFA (and possibly MAFB) levels will be reduced because of their ISR sensitivity. Moreover, I will determine if inhibition of the ISR restores MAFA/MAFB expression and reverses β-cell immaturity in the background of mitochondrial damage.


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: 2025 ( Subtotal = $152,453 )
2025	2025	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	1/6/2025	NON-COMPETING CONTINUATION	$152,453
														Subtotal = $152,453

Issue Date FY: 2024 ( Subtotal = $152,453 )
2024	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/14/2024	NON-COMPETING CONTINUATION	$152,453
														Subtotal = $152,453

Issue Date FY: 2023 ( Subtotal = $142,548 )
2023	2023	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON STREET	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/23/2023	NEW	$142,548
														Subtotal = $142,548

Grand Total All Awards = $447,454

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Elucidating how transcription factors MAFA and MAFB and mitochondrial activity control human Î² cell identity and function

Award Number: K01DK133533

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

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