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: 10618924
• 负责人: Cristina Aguayo-Mazzucato
• 金额: $ 42.7万
• 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/10618924
• 关键词: Achievement; Acute; 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; HIF1A gene; 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; Phenotype; Physiological; Predisposition; Process; Recovery; Reporter; Rodent; Secretory Cell; Stress; Structure of beta Cell of islet; Testing; Therapeutic; Time; Tissues; Translating; Work; age related; biological adaptation to stress; blood glucose regulation; cell type; gain of function; genetic manipulation; glucose metabolism; high body mass index; human old age (65+); improved; in vivo evaluation; indexing; inhibitor; insight; insulin secretion; islet; loss of function; mouse model; novel; pharmacologic; response; senescence; therapeutic target; visual tracking

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.

摘要 这一建议试图阐明β细胞衰老的机制，这是一个衰老的标志，作为 治疗2型糖尿病(T2D)并确定最佳治疗靶点。胰腺分泌胰岛素的β细胞，对 葡萄糖动态平衡，是一种高度分泌的细胞，能够对血糖的微小变化做出反应 营养水平高，并且极易因营养过载而受到压力。我的研究已经确定了老鼠和人类的β- 细胞因胰岛素抵抗(IR)而衰老，导致细胞特性丧失，受损 一种独特的衰老相关分泌表型(SASP)的功能和分泌。此外，我还展示了 感觉神经溶解改善了血糖水平，并恢复了β细胞的功能和特性。我假设 细胞衰老及其SASP是β-细胞功能障碍和丢失的靶向驱动因素。我的目标是 了解β细胞衰老背后的机制，并确定最佳治疗策略。目标1。 确定β细胞衰老的细胞自主驱动因素(S)及其功能效应。基于我们的 在IR和DNA损伤模型中，我们假设周期蛋白依赖的激酶抑制物p21Cip1上调 在β细胞衰老早期，紧随其后的是p16INK4a。将使用遗传获得和功能丧失策略 比较p21Cpi1和p16INK4a对小鼠和人β细胞功能、特性和SASP的影响。 此外，还将精确定位衰老细胞的功能变化。这一目标将定义细胞 驱动β细胞衰老的自主分子机制(S)及其功能后果。目标2. 阐明β-cell SASP的非细胞自主效应。假设是β细胞衰老 可由非细胞自主机制通过SASP因子驱动，能够损害功能 和邻近细胞的基因同一性，并促使它们进入衰老。评估……的效果 在邻近的β细胞上，我们将测试整体和特定选定因素对胰岛素的影响 分泌、衰老状态和基因表达。此外，我们还将测试 用我们的p21Cip1-dTomato Red MIP：GFP报告小鼠在相邻细胞上进行SASP。这一目标将考验 β-cell SASP对非衰老细胞的影响目的3.比较感觉化和感觉化的效果 药物在恢复β细胞功能和身份方面的作用。在我们之前的研究中，感觉分解有效地恢复了 β-细胞的功能和特性，但衰老细胞数量的减少(衰老)可能对 已经不足的β细胞质量，所以也许只抑制它们的SASP(感觉性效应)就可以 产生类似的有益结果。假设变态药物将恢复β细胞的功能并 在不影响细胞质量的情况下识别身份。这一目标将比较感受性药物和感觉性药物对 人类捐赠者的胰岛具有以下一种或多种损害葡萄糖代谢的特征： 年龄较大、IR和T2D。这一目的是为了找出最佳的药理机制，以恢复 功能和细胞特性，无大规模损伤。

项目成果

Heterogeneity of increased biological age in type 2 diabetes correlates with differential tissue DNA methylation, biological variables, and pharmacological treatments.

2 型糖尿病中生物年龄增加的异质性与差异组织 DNA 甲基化、生物变量和药物治疗相关。

• DOI: 10.1007/s11357-023-01009-8
• 发表时间: 2024
• 期刊: GeroScience
• 影响因子: 5.6
• 作者: Cortez,BrianaN;Pan,Hui;Hinthorn,Samuel;Sun,Han;Neretti,Nicola;Gloyn,AnnaL;Aguayo-Mazzucato,Cristina
• 通讯作者: Aguayo-Mazzucato,Cristina