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

• 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
• 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

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。为了更好地理解性别—— 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。