Metabolic Dysfunction

代谢功能障碍

• 批准号: 10561629
• 负责人: JAMES L. KIRKLAND
• 金额: $ 51.23万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10561629
• 关键词: Adipocytes; Adipose tissue; Age; Aging; Aldehydes; Animal Model; Animals; CDKN2A gene; Cardiovascular system; Cell Aging; Cell Transplantation; Cells; Ceramides; Closure by clamp; Cytometry; Dependence; Development; Diabetes Mellitus; Dose; Drug Combinations; Endothelial Cells; Engineering; Enzyme-Linked Immunosorbent Assay; Fatty Acids; Genetic; Glucose; Goals; Human; Immune; Inflammation Mediators; Inflammatory; Insulin; Insulin Resistance; Interleukin-6; Intervention; LOX gene; Label; Lasers; Mediator; Metabolic; Metabolic dysfunction; Metabolic stress; Metabolic syndrome; Metabolism; Methods; Modeling; Molecular; Mus; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Pathway interactions; Phenotype; Production; Radiation; Rattus; Risk Factors; Rodent; Role; System; TNF gene; Testing; Time; Tissues; Transgenic Mice; Translations; Transplantation; activin A; age related; aged; bone; cell type; cellular targeting; chemotherapy; effectiveness testing; healthspan; in vivo; insight; insulin secretion; insulin sensitivity; knock-down; lipid biosynthesis; neutralizing antibody; novel; novel strategies; novel therapeutics; obesity development; osteopontin; pharmacologic; preclinical study; progenitor; senescence; sugar; therapeutic target; tool; transcription factor; translational potential

PROJECT 1: Cellular Senescence and Metabolic Dysfunction – SUMMARY Kirkland/Tchkonia Aging and obesity, both leading risk factors for type 2 diabetes, are associated with senescent cell accumula- tion in adipose and other tissues. In obese mice, we found senescent cells release insulin-resistance-inducing factors and attract and anchor inflammatory immune cells, amplifying metabolic dysfunction; yet was alleviated by reducing, genetically or with senolytics, senescent cell burden. Our hypothesis is that targeting senescent cells can alleviate age-related metabolic dysfunction and its complications. Whether analogous mechanisms operate in age-related metabolic dysfunction must be tested.. Our goal is to discover and develop interventions that target senescent cells to decrease age-related metabolic dysfunction. Aim 1 is to delineate the molecular mechanisms through which senescent cells cause and are induced by metabolic dysfunction. By testing which metabolically-relevant inducers and mediators of metabolic dysfunction cause cellular senescence we will: as- certain the role of cell type, means through which senescence is induced, and metabolic and inflammatory me- diators on the senescence-associated secretory phenotype (SASP) in adipose tissue cells;.test effects of factors on the SASP in already established adipose tissue senescent cells; elucidate effects of the SASP on adipogenesis and insulin responsiveness; identify causal SASP factors using approaches successful in obesi- ty; and test if fat cells themselves can become senescent-like and acquire a SASP. Aim 2 is to determine cel- lular mechanisms through which senescent cells contribute to metabolic dysfunction. Sequences and depot- dependence of adipose tissue senescent and immune cell accumulation with aging will be examined. We will test the role of different cell types and cells made senescent by various inducers on metabolic dysfunction us- ing a novel senescent cell transplant method to pinpoint mechanisms through which senescent cells accentu- ate metabolic stress. We will knock down key SASP factors in the senescent cells being transplanted and compare effects of transplanted cells in mice vs. rats. Aim 3 is to identify and optimize interventions that allevi- ate senescence-related metabolic dysfunction and its complications. We will test the contributions of adipo- cytes featuring senescence, senescent preadipocytes, endothelial cells, and immune cells to age-related meta- bolic dysfunction using transgenic mice (LOX-ATTAC) from which senescent cells can be removed with spatial and temporal selectivity. We will distinguish roles of p16Ink4a vs. p21Cip1 using INK- and p21-ATTAC mice. The role of cellular senescence in age-related metabolic dysfunction in a second species will be tested in an INK- ATTAC rat model. Effects of new compounds developed by Core B, dosing intervals, and senolytic drug com- binations on age-related metabolic dysfunction will be tested first in a novel adipose tissue explant system and then various aged animals. Metabolic and adipose tissue effects of existing and novel senolytics will be com- pared to effects on bone, the cardiovascular system, and muscle in Projects 2-4.

项目1：细胞敏感和代谢功能障碍 - 摘要Kirkland/Tchkonia 衰老和肥胖症是2型糖尿病的主要危险因素，与感觉细胞积累 - 脂肪和其他组织中的作用。在肥胖小鼠中，我们发现感觉细胞释放胰岛素抵抗诱导 因素并吸引和锚定炎性免疫细胞，扩大代谢功能障碍；但是被缓解了 通过减少，一般或使用塞溶剂，感觉细胞负担。我们的假设是针对感官 细胞可以减轻与年龄有关的代谢功能障碍及其并发症。是否具有类似的机制 必须测试与年龄相关的代谢功能障碍。我们的目标是发现和制定干预措施 该靶向感觉细胞可减少与年龄相关的代谢功能障碍。目标1是描绘分子 感觉细胞引起并通过代谢功能障碍引起并诱导的机制。通过测试哪个 代谢功能障碍的代谢诱导剂和介体引起细胞感应，我们将：AS- 确定细胞类型的作用，诱导感应的方法，以及代谢和炎症性的作用 脂肪组织细胞中与感应相关的秘书表型（SASP）的diators；.。 已经建立的脂肪组织感觉细胞中SASP的因素；阐明SASP对 脂肪生成和胰岛素反应；使用方法成功地确定因果关系因素 ty;并测试脂肪细胞本身是否可以变成感觉状并获得SASP。目标2是确定cel- 感官细胞导致代谢功能障碍的乳状机制。序列和沉积 - 将检查脂肪组织感觉和免疫细胞积累随老化的依赖性。我们将 测试各种诱导剂对代谢功能障碍的不同细胞类型和细胞的作用 - 采用一种新型的感觉细胞移植方法来查明机制，感官细胞强调 吃代谢应激。我们将在移植的感觉细胞中击倒关键SASP因子，并 比较小鼠与大鼠的移植细胞的作用。目的3是确定并优化减轻干预措施 ATE与感应相关的代谢功能障碍及其并发症。我们将测试脂肪的贡献 具有感应，感觉前膜细胞，内皮细胞和免疫细胞的细胞对年龄相关的元细胞 使用转基因小鼠（LOX-ATTAC）的Bolic功能障碍，可以通过空间去除感觉细胞 和临时选择性。我们将使用墨水和P21-ATTAC小鼠区分P16INK4A与P21CIP1的角色。这 细胞感应在第二种物种中与年龄相关的代谢功能障碍中的作用将在墨水中测试 ATTAC大鼠模型。核心B开发的新化合物的影响 与年龄相关的代谢功能障碍的分组将首先在新型的脂肪组织外植体系统中进行测试和 然后是各种老年动物。现有和新型鼻溶液的代谢和脂肪组织效应将是 在项目2-4中对骨骼，心血管系统和肌肉的影响。