Role of rs142619613 mutation in MAFLD and hyperglycemia and in African Americans
NIMHD - National Institute on Minority Health and Health Disparities
About This Grant
Abstract: Type 2 diabetes (T2D) and metabolic dysfunction associated fatty liver disease (MAFLD) are two highly-associated metabolic disorders. It is well-documented that race and ethnicity play a significant role in the pathogenesis of MAFLD and T2D. Research indicates that genetic factors, lifestyle, and socioeconomic conditions contribute to the development and progression of MAFLD and T2D across different racial and ethnic groups. However, the underlying mechanisms responsible for the disparities in these diseases among various racial groups remain incompletely understood. Our database mining identified a sequence variant (rs142619613) within the coding region of YY1 gene (Yin Yang 1). The rs142619613 primarily occurs in African Americans (AAs). This nucleotide variant (G-C) leads to Glu47Asp missense mutation, which significantly increased YY1 stability. We further established YY1 as a transcription activator of miR-23b/27b/24. MiR-23b/27b/24 selectively drove AKT phosphorylation while preventing phosphorylation of FoxO1, thereby promoting de novo lipogenesis (DNL) and gluconeogenesis and inhibiting fatty acid oxidation (FAO) and glycolysis. Phenotypically, antagonizing miR- 23b/27b/24 alleviated hepatic insulin resistance, hepatosteatosis, MASH and hyperglycemia. Based on these findings, we hypothesize that rs142619613, by augmenting the YY1-miR-23b/27b/24 axis, selectively drives phosphorylation of AKT and prevents phosphorylation of FoxO1, thereby shifting the metabolic program of the liver towards increased gluconeogenesis and DNL and exacerbating hepatic insulin resistance, hyperglycemia, hepatosteatosis and MASH. The objective of this project is to elucidate the mechanism by which rs142619613 promotes hyperglycemia and MAFLD. Our long-time goal is to elucidate the underlying mechanism of T2D and MAFLD in AAs and to develop YY1 and miR-23b/27b/24 as potential therapeutic targets against both conditions. Three specific aims are designed to test our hypothesis. In Aim 1, we will establish the mechanism by which YY1 promotes hepatic insulin resistance, hepatosteatosis, MASH, and hyperglycemia. Success of this aim will establish gain-of YY1 function and that miR-23b/27b/24 are the downstream player of YY1 to drive DNL and gluconeogenesis and inhibit FAO and glycolysis. In Aim 2, we will determine gain-of function for miR-23b/27b/24 to selectively drive AKT phosphorylation but prevent phosphorylation of FoxO1. Completion of this aim will establish a novel YY1-miR-23b/27b/24 regulatory axis in the control of two central hubs of AKT and FoxO1 signaling, allowing us to explain selective hepatic lipid insulin resistance in which hepatic glucose metabolism becomes unresponsive to insulin but hepatic DNL continues unabated. In Aim 3, we will determine if rs142619613 promotes hepatosteatosis, hyperglycemia and MASH in humanized liver mice. Understanding how T2D and MAFLD develops is of critical importance to design therapeutic strategies to combat both chronic illnesses. The results will provide novel insights into the mechanisms of the prevalence of T2D and MAFLD in AAs, which may lead to rational and targeted therapeutic strategies for both disorders.
Grant Summary
Role of rs142619613 mutation in MAFLD and hyperglycemia and in African Americans is a NIMHD - National Institute on Minority Health and Health Disparities grant providing up to $702K for university, nonprofit, healthcare org. Applications are due 2030-11-30 (open). Check eligibility and apply with FindGrants.
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Up to $702K
2030-11-30
- 1Confirm your organization is eligible for Role of rs142619613 mutation in MAFLD and hyperglycemia and in African Americans from NIMHD - National Institute on Minority Health and Health Disparities, checking organization type, location, and any population or project requirements.
- 2Gather the required documents and information, including your organization details, project plan, and budget figures.
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Role of rs142619613 mutation in MAFLD and hyperglycemia and in African Americans: Frequently Asked Questions
Who is eligible for the Role of rs142619613 mutation in MAFLD and hyperglycemia and in African Americans?
Role of rs142619613 mutation in MAFLD and hyperglycemia and in African Americans is offered by NIMHD - National Institute on Minority Health and Health Disparities and is generally open to university, nonprofit, healthcare org. It is open to organizations nationwide unless the funder specifies otherwise. Review the specific eligibility terms before applying, since funders set their own requirements around organization type, location, and the population or project being served.
How much funding does the Role of rs142619613 mutation in MAFLD and hyperglycemia and in African Americans provide?
Role of rs142619613 mutation in MAFLD and hyperglycemia and in African Americans provides up to $702K per award from NIMHD - National Institute on Minority Health and Health Disparities. Actual award sizes depend on the scope of your project, available program funds, and the number of applicants, so build a budget that reflects realistic, allowable costs rather than the maximum figure.
When is the Role of rs142619613 mutation in MAFLD and hyperglycemia and in African Americans deadline?
Applications for Role of rs142619613 mutation in MAFLD and hyperglycemia and in African Americans are due 2030-11-30 (open). Because deadlines can change, verify the date with the funder, NIMHD - National Institute on Minority Health and Health Disparities, and give yourself enough time to prepare a complete, competitive application before the close date.
How do you apply for the Role of rs142619613 mutation in MAFLD and hyperglycemia and in African Americans?
To apply for Role of rs142619613 mutation in MAFLD and hyperglycemia and in African Americans, confirm your eligibility, gather the required documents, and prepare a narrative and budget that address the funder's priorities. FindGrants guides you step by step and can draft each section, then exports a submission-ready application pack for this grant from NIMHD - National Institute on Minority Health and Health Disparities.