Cytoskeletal functions in cell aging and disease

细胞衰老和疾病中的细胞骨架功能

• 批准号: 9918226
• 负责人: KENNETH G CAMPELLONE
• 金额: $ 15.09万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9918226
• 关键词: Actins; Address; Affect; Age; Aging; American Heart Association; Applications Grants; Autophagocytosis; Bacteria; Biological Assay; Biology; Biology of Aging; Cell Aging; Cell Culture Techniques; Cell membrane; Cell physiology; Cells; Cellular biology; Collaborations; Communicable Diseases; Cytoskeletal Proteins; Cytoskeleton; Data; Defect; Disease; Equilibrium; Estrogen receptor positive; Fibroblasts; Filtration; Genetic; Genetic Diseases; Goals; Golgi Apparatus; Grant; Health; Human; Immune; Immune response; Independent Scientist Award; Infection; Inflammasome; Inflammation; Inflammatory; Interleukin-1 beta; Investigation; K-Series Research Career Programs; Kidney; Kidney Diseases; Kidney Failure; Laboratory Study; Link; Measures; Membrane; Microfilaments; Microtubules; Monomeric GTP-Binding Proteins; Mus; Names; Normal Cell; Organelles; Pathway interactions; Patients; Phased Innovation Awards; Phenotype; Phospholipids; Positioning Attribute; Process; Production; Protein Family; Proteins; Renal function; Research Personnel; Resources; Role; Services; Shapes; Shock; Skeleton; Stimulus; Syndrome; Testing; The Jackson Laboratory; Time; Training; Travel; United States National Institutes of Health; Wiskott-Aldrich Syndrome; Work; aged; base; cell age; cell motility; cytokine; experience; human disease; insight; interest; kidney cell; macrophage; meetings; pathogenic Escherichia coli; podocyte; programs; skills; tool

7. PROJECT SUMMARY Understanding how human cells organize, shape, and move their membrane-bound organelles is one of the most fundamental problems in biology. To address this challenge, my laboratory studies how the actin and microtubule cytoskeletons control membrane remodeling and organelle dynamics. As cells age, their ability to properly regulate these processes changes. This is especially true for kidney cells and immune cells, as a variety of renal and inflammatory diseases develop with age. However, the differences in cytoskeletal functions that give rise to these cellular changes during the aging process are poorly understood. In human cells, actin filament networks are assembled by proteins called nucleation factors from the Wiskott-Aldrich Syndrome Protein (WASP) family. Despite their importance in remodeling membranes during a wide range of processes, these nucleation factors have not been well characterized, especially as they relate to aging and mechanisms of human disease. I have a long-standing interest in determining how the cytoskeleton drives membrane dynamics in normal cells, and how these functions are altered in the context of infectious and genetic diseases. The immediate goal of this Career Development Award is to allow me to initiate another avenue of investigation on the role of the cytoskeleton in cell aging so that I can achieve my long-term goal of leading a lab which studies cytoskeletal functions in health, aging, and disease. These goals will be achieved by completing four specific aims: (1) Define roles for actin nucleation factors and regulators of autophagy in kidney disease, including Nephrocerebellar Syndrome (NCS); (2) Determine functional links between the cytoskeleton, autophagy, cytokine secretion, and inflammation during infection and aging; (3) Deepen my training in the biology of aging through collaborative training experiences at the Jackson Laboratory's Nathan Shock Center of Excellence in the Basic Biology of Aging and at the Center on Aging at the UConn Health Center; (4) Develop into an independent investigator in the basic biology of cell aging. Given my expertise in cytoskeletal biology, plus my existing grant on the role of actin nucleation in autophagy and disease, my lab is uniquely positioned to provide key mechanistic insights into the relationships among actin nucleation factors, autophagy, kidney function, inflammation, and aging.

7。项目摘要 了解人类细胞如何组织，塑造和移动膜结合的细胞器是其中之一 生物学中最基本问题。为了应对这一挑战，我的实验室研究肌动蛋白和 微管细胞骨架控制膜重塑和细胞器动力学。随着细胞的年龄，它们的能力 正确调节这些过程的变化。对于肾细胞和免疫细胞尤其如此，作为一个 随着年龄的增长，肾脏和炎症性疾病的多种多样。但是，细胞骨架功能的差异 在衰老过程中引起这些细胞变化的理解很少。在人类细胞中，肌动蛋白 细丝网络由Wiskott-Aldrich综合征称为成核因子的蛋白质组装 蛋白质（WASP）家族。尽管它们在各种过程中都在重塑膜中的重要性，但 这些成核因子尚未得到很好的特征，尤其是在与衰老和机制相关时 人类疾病。我对确定细胞骨架如何驱动膜有兴趣 正常细胞的动力学以及在感染和遗传疾病的背景下如何改变这些功能。 该职业发展奖的直接目标是让我启动另一条途径 研究细胞骨架在细胞衰老中的作用，以便我可以实现领导A的长期目标 研究了健康，衰老和疾病中细胞骨架功能的实验室。这些目标将通过 完成四个具体目标：（1）定义肌动蛋白成核因子和自噬的调节剂的作用 肾脏疾病，包括肾脑综合征（NCS）； （2）确定 感染和衰老期间的细胞骨架，自噬，细胞因子分泌和炎症； （3）加深我 通过在杰克逊实验室的内森（Nathan）的合作培训经验中培训衰老的生物学 衰老基本生物学和UConn Health衰老中心的卓越中心 中心; （4）发展成为细胞衰老基本生物学的独立研究者。考虑到我的专业知识 细胞骨架生物学，以及我现有关于肌动蛋白成核在自噬和疾病中作用的赠款，我的实验室是 独特的位置，以提供对肌动蛋白成核因子之间关系的关键机理见解， 自噬，肾功能，炎症和衰老。