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.

项目摘要截至 2018 年，已有 3030 万美国人被诊断患有糖尿病（占美国人口的 10%）男性性别偏见）。它与许多慢性疾病密切相关，如心脏病、中风和癌症，使糖尿病成为发病率和死亡率的主要危险因素。在所有形式的糖尿病中，无法维持正常的血糖水平是由于体内产生胰岛素的 B 细胞进行性功能障碍和最终丧失所致。胰腺。由于标准疗法的治疗失败率很高，因此开发新的治疗方法保留甚至增强 B 细胞功能是首要任务。此外，男性之间新陈代谢的差异健康老龄化和疾病期间的女性受到赞赏，但了解甚少。胰腺 B 细胞需要几个关键因素才能适当分泌胰岛素。 MafA 就是这样一个因素，成熟 B 细胞功能的基础转录因子。 b 细胞中人类 MafA (MAFA) 的早期缺失 2 型糖尿病患者强调了其对人类 B 细胞健康的重要性。此外，一种自然发生的、最近发现 MAFA (S64F MAFA) 基因突变使携带者易患家族性、成人发病糖尿病或低血糖（低血糖）。奇怪的是，S64F MAFA 相关的糖尿病在很大程度上是男性更常见，而女性往往出现低血糖。为了更好地了解性别—— 由于该变异的依赖性效应，我们生成了携带该突变的小鼠模型。该模型显示了预期在人类中观察到的性别依赖性效应，表明小鼠和人类之间存在类似的机制。雄性 S64F MAFA 小鼠由于广泛的、过早的 B 细胞老化和衰老而出现高血糖，而雌性 S64F MAFA 小鼠出现低血糖的机制尚未明确。然而，我们的初步研究表明，S64F MAFA 在女性体内产生不同的 b 细胞亚型，其中之一是功能亢进。综上所述，这些结果表明 S64F MAFA 可以引起不同的 b 细胞反应产生性别依赖性疾病：糖尿病（b 细胞功能减退）和低血糖（b 细胞功能亢进）。这项研究将鉴定并比较男性和女性对 S64F MAFA 的不同分子反应。小鼠和人类中的雌性 B 细胞，以了解人类特有的性别依赖性 B 细胞反应 b 细胞。我们将首先使用渗透性、原理验证的 S64F MAFA 小鼠模型，该模型模仿了几种人类疾病的各个方面，通过单细胞转录组学鉴定不同的 B 细胞群。例如，早衰特征的多样性与衰老男性 S64F MAFA 中观察到的功能障碍有关 b 细胞。然后我们将研究 S64F MAFA 蛋白的分子和功能反应使用新型伪胰岛技术识别靶标的转基因男性和女性人类 B 细胞人类 B 细胞功能所独有。总之，我们的工作将增进对性别依赖的基本理解人类 b 细胞反应。男性相对脆弱性和女性抵抗力的潜在机制可以利用该模型中的糖尿病来开发适合个体的治疗方法。