Elucidating and targeting beta-cell senescence and its SASP

阐明和靶向 β 细胞衰老及其 SASP

• 批准号: 10420268
• 负责人: Cristina Aguayo-Mazzucato
• 金额: $ 38.43万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-10 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10420268
• 关键词: Achievement; Acute; Age; Aging; B-Lymphocytes; Beta Cell; Biology; Blood Glucose; CDKN2A gene; Cell Aging; Cell physiology; Cells; Characteristics; Coupled; Cyclin-Dependent Kinase Inhibitor; DNA Damage; Data; Development; Disease; Drug Targeting; Enzyme-Linked Immunosorbent Assay; Fatty acid glycerol esters; Functional disorder; Gene Expression; Genes; Genetic; Goals; Human; Impairment; In Vitro; Insulin; Insulin Resistance; Knowledge; Liver; Measurement; Metabolic; Modeling; Molecular; Mus; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Outcome; Pancreas; Pathway interactions; Peripheral; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiological; Play; Process; Recovery; Reporter; Rodent; Role; Secretory Cell; Stress; Structure of beta Cell of islet; Testing; Therapeutic; Time; Tissues; Translating; Work; age related; base; biological adaptation to stress; blood glucose regulation; cell type; genetic manipulation; glucose metabolism; high body mass index; improved; in vivo evaluation; indexing; inhibitor; insight; insulin secretion; islet; loss of function; mouse model; novel; response; senescence; therapeutic target

Abstract This proposal seeks to elucidate the mechanisms of β-cell senescence, an aging hallmark, as a contributor to type 2 diabetes (T2D) and identify optimal therapeutic targets. Pancreatic insulin secreting β-cells, crucial to glucose homeostasis, are heavily secretory cells, equipped to respond to small changes in blood glucose levels and highly susceptible to stress by nutrient overload. My work has identified that mouse and human β- cells undergo senescence in response to insulin resistance (IR), leading to loss of cellular identity, impaired function and secretion of a unique senescence-associated secretory phenotype (SASP). Additionally, I showed that senolysis improved blood glucose levels and recovery of β-cell function and identity. I hypothesize that cellular senescence and its SASP are targetable drivers of β-cell dysfunction and loss. My goals are to understand the mechanisms behind β-cell senescence and identify the optimal therapeutic strategy. Aim 1. Identify the cell autonomous driver(s) of β-cell senescence and its functional effects. Based on our models of IR and DNA damage, we hypothesize that cyclin-dependent kinase inhibitor p21Cip1 is upregulated early in β-cell senescence and is followed by p16Ink4a. Genetic gain- and loss-of-function strategies will be used to compare the effects of p21Cpi1 and p16Ink4a on mouse and human β-cell function, identity and SASP. Additionally, the functional changes of senescent cells will be pinpointed. This aim will define the cell autonomous molecular mechanism(s) that drive β-cell senescence and its functional consequences. Aim 2. Elucidate the non-cell autonomous effects of the β-cell SASP. The hypothesis is that β-cell senescence can be driven by a non-cell autonomous mechanism through SASP factors, capable of impairing the function and gene identity of neighboring cells and precipitating their entry into senescence. To evaluate the effects of SASP upon neighboring β-cells, we will test the effects of the overall and specific selected factors on insulin secretion, senescence status and gene expression. Additionally, we will test the temporo-spatial effects of SASP on neighboring cells using our p21Cip1-dTomato Red MIP:GFP reporter mice. This aim will test the effects of β-cell SASP on non-senescent cells. Aim 3. Compare the effects of senolytic and senomorphic drugs in the recovery of β-cell function and identity. In our previous studies, senolysis effectively restored β-cell function and identity but a decrease in the number of senescent cells (senolysis) may be detrimental to an already inadequate beta cell mass, so perhaps only inhibiting their SASP (senomorphic effect) would render similar beneficial results. The hypothesis is that senormorphic drugs will restore β-cell function and identity without impacting cell mass. This aim will compare the effects of senolytic and senomorphic drugs on islets of human donors that have one or more of the following characteristics impairing glucose metabolism: older age, IR and T2D. This aim seeks to identify the optimal pharmacological mechanisms to recover the function and cellular identity without mass impairment.

抽象的 该提案旨在阐明β细胞感应的机制，即老化的标志，作为促成 2型糖尿病（T2D）并确定最佳的治疗靶点。胰腺胰岛素分泌β细胞，至关重要 葡萄糖体内稳态，是秘书细胞，配备了小小的葡萄糖变化 水平，高度容易受到养分超负荷的压力。我的工作已经确定了小鼠和人β- 细胞对胰岛素抵抗（IR）的响应经历感染，导致细胞身份的丧失，受损 独特的感应相关秘书表型（SASP）的功能和分泌。另外，我表明 鼻溶液改善了血糖水平以及β细胞功能和身份的恢复。我假设这一点 细胞感应及其SASP是β细胞功能障碍和损失的靶向驱动因素。我的目标是 了解β细胞感应的机制，并确定最佳的治疗策略。目标1。 确定β细胞感应的细胞自主驱动器及其功能效应。基于我们 IR和DNA损伤的模型，我们假设细胞周期蛋白依赖性激酶抑制剂P21CIP1已更新 在β细胞感应中早期，然后是p16Ink4a。将使用遗传增益和功能丧失策略 比较p21cpi1和p16ink4a对小鼠和人β细胞功能，身份和SASP的影响。 此外，将确定感觉细胞的功能变化。这个目标将定义单元格 驱动β细胞感应及其功能后果的自主分子机制。目标2。 阐明β细胞SASP的非电池自主效应。假设是β细胞的感应 可以通过SASP因素来驱动非细胞自主机制，能够损害该功能 以及相邻细胞的基因身份，并沉淀出它们进入感应。评估 SASP在相邻的β细胞上，我们将测试整体和特定选择因素对胰岛素的影响 分泌，感应状态和基因表达。此外，我们将测试 使用我们的P21CIP1-DTOMATO红色MIP：GFP报告基因小鼠在相邻细胞上的SASP。这个目标将测试 β细胞SASP对非渗入细胞的影响。目标3。比较鼻溶剂和鼻型的影响 恢复β细胞功能和身份的药物。在我们以前的研究中，鼻溶液有效地恢复了 β细胞的功能和身份，但可以确定感觉细胞数量的数量（Senolsesy）可以确定为 β细胞量已经不足，因此也许只能抑制其SASP（鼻型效应） 产生类似的有益结果。假设是，鼻型药物将恢复β细胞功能和 身份不影响细胞质量。这个目标将比较鼻溶剂和鼻型药物对 具有以下一个或多个特征损害葡萄糖代谢的人类捐助者的胰岛： 年龄较大，IR和T2D。此目标旨在确定最佳药物机制以恢复 功能和细胞身份而没有质量损害。