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Examining how the novel S64F MAFA variant produces glucose intolerance or hypoglycemia in a sex-dependent manner

研究新型 S64F MAFA 变体如何以性别依赖性方式产生葡萄糖不耐受或低血糖

基本信息

批准号：
10641724
负责人：
Jeeyeon Cha
金额：
$ 15.84万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10641724
关键词：
10 year old Acute Adult Aging American Apoptosis Automobile Driving B-Lymphocytes Beta Cell Birth Blood Glucose Bromodomains and extra-terminal domain inhibitor Cell Aging Cell Cycle Regulation Cell physiology Cells Characteristics Chronic Chronic Disease Classification Collection Curiosities DNA Sequence Alteration Data Set Development Diabetes Mellitus Diagnosis Disease Exhibits Family Female Functional disorder Gene Expression Glucose Glucose Intolerance Health Heterogeneity Hormones Human Hyperglycemia Hypoglycemia Immunocompromised Host Impairment Individual Insulin Investigation Islets of Langerhans Life Link Malignant Neoplasms Mature B-Lymphocyte Mediating Metabolism Minor Modeling Molecular Molecular Profiling Morbidity - disease rate Mus Mutation Myocardial Infarction Non-Insulin-Dependent Diabetes Mellitus Pancreas Pathogenicity Patients Phenotype Phenylalanine Physiological Point Mutation Population Positioning Attribute Premature aging syndrome Production Property Proteins Publishing Resistance Risk Factors Rodent Model Serine Sex Bias Sex Differences Signal Transduction Stroke Structure of beta Cell of islet Technology Testing Transcription Coactivator Transplantation Treatment Failure Variant Woman Work age related aged blood glucose regulation burden of illness differential expression healthy aging human disease human female improved in vivo individualized medicine insight insulin secretion insulinoma islet male men mortality mouse model mutant novel novel therapeutic intervention pathological aging postnatal premature preservation response senescence sex sexual dimorphism single-cell RNA sequencing therapy development transcription factor transcriptomics

项目摘要

PROJECT ABSTRACT As of 2018, 30.3 million Americans have been diagnosed with diabetes (10% of the U.S. population with a male sex bias). Its close associations with many chronic diseases, such as heart attacks, strokes, and cancers, make diabetes a leading risk factor for morbidity and mortality. In all forms of diabetes, the inability to maintain normal glucose levels results from progressive dysfunction and eventual loss of insulin-producing b-cells in the pancreas. With high rates of treatment failure on standard therapy, developing new therapeutic approaches to preserve or even enhance b-cell function is a priority. Furthermore, differences in metabolism between men and women during healthy aging and disease are appreciated but poorly understood. Pancreatic b-cells require several key factors to appropriately secrete insulin. One such factor is MafA, a transcription factor fundamental to mature b-cell function. The early loss of human MafA (MAFA) in b-cells in patients with type 2 diabetes highlights its importance to human b-cell health. In addition, a naturally occurring, genetic mutation in MAFA (S64F MAFA) was recently identified to predispose carriers to either familial, adult- onset diabetes or hypoglycemia (low blood glucose). Curiously, S64F MAFA-associated diabetes is much more prevalent in men while women tend to present with hypoglycemia. To better understand the sex- dependent effects of this variant, we generated a mouse model harboring this mutation. This model shows the expected sex-dependent effects seen in humans, suggesting similar mechanisms between mice and humans. Male S64F MAFA mice were hyperglycemic due to widespread, premature b-cell aging and senescence, while female S64F MAFA mice were hypoglycemic by a mechanism which is not yet clearly defined. However, our preliminary studies suggest that S64F MAFA creates different b-cell subtypes in females, one of which is hyperfunctional. Taken together, these results suggest that S64F MAFA can incur diverse b-cell responses to produce sex-dependent diseases: diabetes (b-cell hypofunction) and hypoglycemia (b-cell hyperfunction). This investigation will identify and compare the diverse molecular responses to S64F MAFA in male and female b-cells across mice and humans to understand the sex-dependent, b-cell responses unique to human b-cells. We will first use the penetrant, proof-of-principle S64F MAFA mouse model which mimics several aspects of human disease to identify the diverse b-cell populations by single cell transcriptomics. For example, diversity in premature aging signatures will be related to the dysfunction seen in senescent, male S64F MAFA b-cells. We will then investigate the molecular and functional responses to the S64F MAFA protein in genetically modified, male and female human b-cells using novel pseudoislet technology to identify targets unique to human b-cell function. In sum, our work will advance fundamental understanding of sex-dependent b-cell responses in humans. Mechanisms underlying a relative male vulnerability and female resistance to diabetes in this model can be harnessed to develop therapies tailored to the individual.

项目摘要