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细胞的质量和功能适应生物体的胰岛素需求，以维持整个机体的胰岛素水平。 广泛的病理生理学，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， 随着2型糖尿病（T2 D）的发作，功能适应在临床上变得明显。与继续 肥胖增加，寻求调节β细胞适应的新的治疗上易处理的途径， 逆转T2 D中的β细胞功能障碍。 Notch是一个高度保守的蛋白质家族，对细胞命运决策至关重要;在发育中的内分泌系统中， 在胰腺中，Notch信号调节β细胞分化，但对成熟胰腺中Notch的作用知之甚少。 组织.我们最近发现，Notch信号在发育完全的β细胞中以低水平存在，但 在高葡萄糖培养的或从肥胖小鼠分离的胰岛中增加。持续性β细胞Notch信号传导 似乎对功能有害，因为我们观察到葡萄糖耐量的改善与β细胞的遗传抑制 切口行动。相反，强迫Notch激活会损害葡萄糖刺激的胰岛素分泌（GSIS）， 分离的小鼠或人胰岛，并在β细胞特异性Notch功能获得性小鼠中诱导葡萄糖耐受不良。 在目标1中，我们研究了β细胞Notch活性增加的机制，利用数据显示β细胞Notch活性增加。 Notch配体Jagged 1的表达与Notch活性一起跟踪。我们测试β细胞锯齿状蛋白1是否 这是肥胖症中适应不良β细胞Notch反应的必要和充分条件。在目标2中，我们处理 Notch引起的GSIS缺陷的机制。在关键的初步数据中，我们发现Notch诱导降解， MafA，β细胞成熟的关键调节因子在T2 D中被破坏。我们还观察到新的MafA乙酰化，阻断 Notch活动。我们现在研究MafA的稳定性和活性是否依赖于乙酰化，并阐明 这些翻译后修饰背后的分子机制。我们还测试了Notch是否会影响 稳定性和乙酰化密切相关的转录因子，MafB。最后，在目标3中，我们测试了影响 我们鉴定的NOTCH-MAFA/B轴在人β细胞对葡萄糖的转录和功能反应中的作用，以及 作为对人胰岛中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物，以及 可能为T2 D患者的护理开发新的治疗方向。