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 细胞衰老（衰老标志）的机制，作为衰老的贡献者 2 型糖尿病 (T2D) 并确定胰腺胰岛素分泌 β 细胞的最佳治疗靶点，这对治疗至关重要。 葡萄糖稳态，是大量分泌细胞，能够对血糖的微小变化做出反应 我的研究发现，小鼠和人类的 β- 水平极易受到营养过剩的压力。 细胞因胰岛素抵抗（IR）而发生衰老，导致细胞身份丧失、受损 独特的衰老相关分泌表型（SASP）的功能和分泌。 衰老作用改善了血糖水平并恢复了 β 细胞的功能和身份。 细胞衰老及其 SASP 是 β 细胞功能障碍和丧失的目标驱动因素。 了解 β 细胞衰老背后的机制并确定最佳治疗策略。 根据我们的研究，确定 β 细胞衰老的细胞自主驱动因素及其功能效应。 在 IR 和 DNA 损伤模型中，我们发现细胞周期蛋白依赖性激酶抑制剂 p21Cip1 上调 β 细胞衰老早期，随后是 p16Ink4a，将使用遗传功能获得和丧失策略。 比较 p21Cpi1 和 p16Ink4a 对小鼠和人类 β 细胞功能、身份和 SASP 的影响。 此外，衰老细胞的功能变化将被精确定位，这一目标将定义细胞。 驱动 β 细胞衰老的自主分子机制及其功能后果 目标 2。 阐明 β 细胞 SASP 的非细胞自主效应 假设是 β 细胞衰老。 可以通过 SASP 因子由非细胞自主机制驱动，能够损害功能 和邻近细胞的基因特性并促进它们进入衰老状态以评估其影响。 SASP对邻近β细胞的影响，我们将测试整体和特定选定因素对胰岛素的影响 此外，我们将测试其时空效应。 使用我们的 p21Cip1-dTomato Red MIP:GFP 报告小鼠对邻近细胞进行 SASP 该目标将测试 SASP。 β-细胞 SASP 对非衰老细胞的影响 目标 3. 比较 senolytic 和 senomorphic 的效果。 在我们之前的研究中，药物可以有效恢复β细胞的功能和身份。 β 细胞的功能和特性，但衰老细胞数量的减少（衰老作用）可能会令 β 细胞质量已经不足，因此也许只有抑制其 SASP（senomorph 效应）才能 产生类似的有益结果的假设是，sormorphic 药物将恢复 β 细胞功能和 该目标将比较 senolytic 和 senomorphic 药物对细胞质量的影响。 具有以下一项或多项损害葡萄糖代谢特征的人类捐赠者的胰岛： 老年、IR 和 T2D 这一目标旨在确定恢复的最佳药理学机制。 功能和细胞特性而无质量损伤。