Cytoskeletal functions in cell aging and disease

7.项目总结 了解人类细胞如何组织、塑造和移动它们的膜结合细胞器是 生物学中最基本的问题。为了应对这一挑战，我的实验室研究了肌动蛋白和 微管细胞骨架控制细胞膜重塑和细胞器动力学。随着细胞的老化，它们的能力 适当地规范这些过程的变化。对于肾脏细胞和免疫细胞来说尤其如此，因为 各种肾脏疾病和炎症性疾病随着年龄的增长而发展。然而，细胞骨架功能的差异 在衰老过程中引起这些细胞变化的原因还知之甚少。在人类细胞中，肌动蛋白 细丝网络由来自Wiskott-Aldrich综合征的称为核因子的蛋白质组装而成 蛋白质(WASP)家族。尽管它们在广泛的过程中对膜的重塑很重要， 这些成核因素还没有得到很好的表征，特别是当它们与衰老和机制有关时 人类疾病的威胁。我对确定细胞骨架如何驱动细胞膜一直很感兴趣 正常细胞的动力学，以及这些功能如何在传染病和遗传病的背景下改变。 这个职业发展奖的直接目标是让我开创另一条途径 研究细胞骨架在细胞衰老中的作用，以便实现我领导一个 研究细胞骨架在健康、衰老和疾病中的功能的实验室。这些目标将通过以下方式实现 完成四个具体目标：(1)确定肌动蛋白成核因子和自噬调节因子在 肾脏疾病，包括肾小脑综合征(NCS)；(2)确定 感染和衰老过程中的细胞骨架、自噬、细胞因子分泌和炎症；(3)加深我的 在杰克逊实验室的内森通过协作培训体验进行衰老生物学培训 老年基础生物学和康涅狄格州大学健康老年中心的卓越震撼中心 (4)发展成为细胞衰老基础生物学的独立研究者。鉴于我在 细胞骨架生物学，加上我现有的关于肌动蛋白核化在自噬和疾病中的作用的拨款，我的实验室是 独特的定位，为肌动蛋白成核因素之间的关系提供关键的机械性见解， 自噬、肾功能、炎症和衰老。

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.