Beta cell Notch activity in Type 2 Diabetes

2 型糖尿病中的 Beta 细胞 Notch 活性

• 批准号: 10592434
• 负责人: Utpal Pajvani
• 金额: $ 56.53万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10592434
• 关键词: Acetylation; Acetyltransferase; Activities of Daily Living; Address; Adult; Affect; Aging; Antibodies; Architecture; Beta Cell; Biological; Cell Differentiation process; Cells; Cellular biology; Chromatin; Clinical; Data; Decision Making; Defect; Development; Embryo; Functional disorder; Gene Expression; Genetic; Genetic Transcription; Glucose; Glucose Intolerance; Goals; Heterogeneity; High Fat Diet; Human; Hyperglycemia; Impairment; Insulin; Insulin Resistance; Islets of Langerhans; Knock-out; Knockout Mice; Ligands; Lysine; Mediating; Metabolic Diseases; Methods; Modeling; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Organism; Pancreas; Pathology; Pathway interactions; Patients; Post-Translational Protein Processing; Pregnancy; Protein Family; Proteins; Publishing; Role; Signal Pathway; Signal Transduction; Testing; Therapeutic; Thinness; Tissues; Transactivation; Transgenic Organisms; Work; cell stroma; db/db mouse; diabetes mellitus therapy; direct patient care; euglycemia; expectation; feeding; functional adaptation; gain of function; glucose tolerance; improved; inhibitor; insulin secretion; islet; knock-down; leptin receptor; liquid chromatography mass spectrometry; loss of function; mutant; notch protein; novel; novel therapeutics; postnatal human; receptor; response; single-cell RNA sequencing; stressor; transcription factor; transcriptome sequencing

Project Abstract β cell mass and function adapts to the insulin requirements of the organism to maintain euglycemia across a wide range of pathophysiology, such as insulin resistance induced by obesity, pregnancy or aging. Although molecular mechanisms that enable β cell adaptation to these stressors are not yet fully understood, insufficient functional adaptation becomes clinically apparent with the onset of Type 2 Diabetes (T2D). With the continued increase in obesity, novel therapeutically-tractable pathways that regulate β cell adaptation are sought to reverse β cell dysfunction in T2D. Notch is a highly conserved family of proteins critical for cell fate decision-making; in the developing endocrine pancreas, Notch signaling regulates β cell differentiation, but less is known about Notch action in mature tissue. We have recently shown that Notch signaling is present at low levels in fully developed β cells, but increased in islets cultured in high glucose or isolated from obese mice. Persistent β cell Notch signaling appears detrimental to function, as we observed improved glucose tolerance with genetic inhibition of β cell Notch action. Conversely, forced Notch activation impaired glucose-stimulated insulin secretion (GSIS) in isolated mouse or human islets, and induced glucose intolerance in β cell-specific Notch gain-of-function mice. In Aim 1, we investigate mechanism of increased β cell Notch activity, leveraging data showing that β cell expression of the Notch ligand, Jagged1, tracks with Notch activity. We test whether β cell Jagged1 is necessary and sufficient for the maladaptive β cell Notch response in obesity. In Aim 2, we address mechanism of Notch-induced GSIS defects. In key preliminary data, we found that Notch induces degradation of MafA, a key regulator of β cell maturity disrupted in T2D. We also observe novel MafA acetylations, blocked by Notch activity. We now study whether MafA stability and activity is dependent on acetylations, and elucidate the molecular machinery underlying these post-translational modifications. We also test whether Notch impacts stability and acetylation of the closely related transcription factor, MafB. Finally, in Aim 3, we test implications of our identified NOTCH-MAFA/B axis in human β cell transcriptional and function response to glucose, as well as effects on β cell heterogeneity in human islets. Achieving the goals of this application will determine upstream signals for Notch activation, downstream effectors of Notch-induced β cell dysfunction, and potentially develop novel therapeutic directions for the care of patients with T2D.

项目摘要 β细胞质量和功能适应生物体的胰岛素要求，以维持跨A 广泛的病理生理学，例如肥胖，妊娠或衰老引起的胰岛素抵抗。虽然 使β细胞适应这些应激源的分子机制尚未完全理解，不足 随着2型糖尿病（T2D）的发作，功能适应在临床上变得显而易见。继续进行 肥胖症的增加，调节β细胞适应的新型可热吸收途径被感觉到 T2D中的反向β细胞功能障碍。 Notch是对细胞命运决策至关重要的高度保守的蛋白质家族。在发育中的内分泌中 胰腺，Notch信号传导调节β细胞的分化，但对成熟的Notch作用知之甚少 组织。我们最近表明，在完全发达的β细胞中，凹槽信号在低水平上存在，但是 在高葡萄糖或从肥胖小鼠中分离的胰岛中增加。持续的β细胞Notch信号传导 表观确定功能的确定，因为我们观察到葡萄糖的耐受性提高了β细胞的遗传抑制 缺口行动。相反，强迫Notch激活损害了葡萄糖刺激的胰岛素分泌（GSIS） 分离的小鼠或人类胰岛，并在β细胞特异性功能获得的小鼠中诱导葡萄糖肠球。 在AIM 1中，我们研究了增加β细胞缺陷活性的机制，利用数据表明β细胞 Notch配体的表达JAGGED1具有Notch活性的轨道。我们测试β细胞是否锯齿状1是 肥胖症中适应不良的β细胞缺口反应的必要和足够。在AIM 2中，我们解决 Notch诱导的GSIS缺陷的机制。在关键的初步数据中，我们发现Notch引起降解 MAFA，是T2D中破坏β细胞成熟度的关键调节剂。我们还观察到新型的MAFA乙酰化，阻塞 通过Notch活动。现在，我们研究MAFA稳定性和活动是否取决于乙酰化并阐明 这些翻译后修饰为基础的分子机制。我们还测试Notch是否影响 密切相关转录因子的稳定性和乙酰化MAFB。最后，在AIM 3中，我们测试含义 人类β细胞转录和对葡萄糖的功能响应中所鉴定的Notch-MAFA/B轴 随着人类胰岛中β细胞异质性的影响。实现此应用程序的目标将决定 Notch激活的上游信号，Notch诱导的β细胞功能障碍的下游效应以及 有可能开发出新的治疗方向，以护理T2D患者。