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Beta cell Notch activity in Type 2 Diabetes

2 型糖尿病中的 Beta 细胞 Notch 活性

基本信息

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
项目类别：
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

项目摘要

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