Cytoskeletal control of membrane remodeling

膜重塑的细胞骨架控制

• 批准号: 9254568
• 负责人: KENNETH G CAMPELLONE
• 金额: $ 28.54万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9254568
• 关键词: ANGPTL2 gene; Actins; Address; Affinity; Autophagocytosis; Autophagosome; Binding; Biochemical; Biogenesis; Biological Assay; Biology; Blindness; C-terminal; Cardiovascular Abnormalities; Cell Line; Cell physiology; Cells; Cessation of life; Childhood; Chromatography; Complex; Cultured Cells; Cytoskeleton; DNA Sequence Alteration; Defect; Development; Diagnostic; Disease; Family member; Fibroblasts; Frameshift Mutation; Genes; Goals; Guanosine Triphosphate Phosphohydrolases; Health; Hereditary Disease; Homeostasis; Human; Immunologic Deficiency Syndromes; In Vitro; Laboratory Study; Language; Lead; Liposomes; Mass Spectrum Analysis; Measures; Membrane; Microcephaly; Microfilaments; Microtubules; Molecular; Monomeric GTP-Binding Proteins; Muscle hypotonia; Mutation; N-terminal; Neurodevelopmental Disorder; Neurologic; Neurons; Organelles; Patients; Phospholipid Interaction; Phospholipids; Play; Process; Protein Complex Subunit; Protein Family; Proteins; RNA Interference; Recombinants; Research; Role; Seizures; Shapes; System; Testing; Vacuole; Visual impairment; Wiskott-Aldrich Syndrome; Work; brain tissue; disease-causing mutation; human disease; insight; member; mutant; nervous system disorder; neuropathology; professor; public health relevance; reconstitution; tool; trafficking

DESCRIPTION (provided by applicant): 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. Because the functions of the actin cytoskeleton are crucial for so many cellular and organismal functions, a variety of immunodeficiencies, cardiovascular abnormalities, and neurological defects arise when actin dynamics is disrupted. 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 trafficking processes, these nucleation factors have not been well characterized, especially as they relate to mechanisms of human disease. In this proposal, we describe a new genetic disorder that results in a severe neurodevelopmental delay (SND) in humans. This condition is caused by a mutation in WHAMM, a gene encoding one such nucleation factor, and is accompanied by defects in autophagy, a process by which cells degrade their cytoplasmic components. Many neurological and developmental diseases are associated with altered autophagic functions, but the role of the cytoskeleton in autophagosome biogenesis and flux has been largely unexplored. To better understand the role that cytoskeleton-driven membrane remodeling plays in human health, the broad long-term goal of my research is to determine how nucleation factors control membrane dynamics and how alterations in their functions contribute to disease. The specific goals of this project are to determine how WHAMM and other cytoskeleton-associated proteins normally drive remodeling of autophagosome membranes, and to decipher how these functions are altered in SND. These goals will be achieved by completing three specific aims: (1) Determine the molecular and cellular defects that lead to SND, (2) Define the composition and activities of the native WHAMM complex, and (3) Assess the role of small GTPases and phospholipids in cytoskeletal coordination. We hope that our studies will eventually lead to advances in diagnostic tools or therapies for diseases caused by mutations in WHAMM. But since our results will have a broad impact on understanding the cytoskeletal mechanisms that control autophagy, we believe that they may also lead to translational benefits for patients with many other illnesses.

描述（由申请人提供）：了解人类细胞如何组织、塑造和移动其膜结合细胞器是生物学中最基本的问题之一。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如何控制膜重塑和细胞器动力学。由于肌动蛋白细胞骨架的功能对于许多细胞和有机体功能至关重要，因此当肌动蛋白动力学受到破坏时，会出现多种免疫缺陷、心血管异常和神经系统缺陷。在人类细胞中，肌动蛋白丝网络由来自 Wiskott-Aldrich 综合征蛋白 (WASP) 家族的成核因子蛋白组装。尽管它们在广泛的运输过程中重塑膜中发挥着重要作用，但这些成核因子尚未得到很好的表征，特别是当它们与人类疾病机制相关时。在这项提案中，我们描述了一种新的遗传性疾病，它会导致人类严重的神经发育迟缓（SND）。这种情况是由 WHAMM（一种编码此类成核因子的基因）突变引起的，并伴有自噬缺陷，自噬是细胞降解其细胞质成分的过程。许多神经系统和发育疾病与自噬功能改变有关，但细胞骨架在自噬体生物发生和通量中的作用很大程度上尚未被探索。为了更好地了解细胞骨架驱动的膜重塑在人类健康中发挥的作用，我研究的广泛长期目标是确定成核因子如何控制膜动力学以及其功能的改变如何导致疾病。该项目的具体目标是确定 WHAMM 和其他细胞骨架相关蛋白通常如何驱动自噬体膜的重塑，并破译这些功能在 SND 中如何改变。这些目标将通过完成三个具体目标来实现：(1) 确定导致 SND 的分子和细胞缺陷，(2) 定义天然 WHAMM 复合物的组成和活性，以及​​ (3) 评估小 GTP 酶和磷脂在细胞骨架协调中的作用。我们希望我们的研究最终能够推动 WHAMM 突变引起的疾病的诊断工具或治疗方法的进步。但由于我们的结果将对理解控制自噬的细胞骨架机制产生广泛影响，因此我们相信它们也可能为患有许多其他疾病的患者带来转化益处。