INVESTIGATING THE ROLE OF THE CYTOSKELETON IN NEURODEGENERATION

研究细胞骨架在神经变性中的作用

• 批准号: 10534590
• 负责人: Morgan Catherine Stephens
• 金额: $ 4.68万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10534590
• 关键词: 70-kDa Ribosomal Protein S6 Kinases; Actins; Adult; Affect; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; American; Automobile Driving; Autophagocytosis; Behavior; Behavioral; Biochemical; Biological Assay; Biological Models; Brain; Cause of Death; Cell model; Cells; Clinical; Color; Communication; Complex; Cytoskeleton; Data; Dementia; Dendritic Spines; Deposition; Development; Disease; Disease Progression; Distal; Drosophila genus; Environment; Etiology; Genes; Genetic; Genetic Screening; Goals; Harvest; Histologic; Histology; Human; Human Cell Line; Huntington Disease; Impairment; In Vitro; LIM Domain; LIMK1 gene; Lysosomes; Malignant Neoplasms; Measures; Mediating; Microfilaments; Microscopy; Modeling; Modification; Molecular; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuronal Dysfunction; Neurons; Parkinson Disease; Pathogenesis; Pathology; Pathway interactions; Phase; Phosphotransferases; Prevalence; Process; Proteins; Regulation; Research; Resolution; Rod; Role; Senile Plaques; Societies; Synapses; System; Tauopathies; Techniques; Therapeutic; Therapeutic Intervention; Transmission Electron Microscopy; Ubiquitin; United States; Vesicle; Western Blotting; actin depolymerizing factor; attenuation; brain tissue; cofilin; combat; density; depolymerization; disability; extracellular; histological studies; hyperphosphorylated tau; improved; in vitro Assay; in vivo; induced pluripotent stem cell; insight; knock-down; misfolded protein; mouse model; multicatalytic endopeptidase complex; nerve stem cell; neurodegenerative phenotype; neuroinflammation; neuropathology; neurotoxic; new therapeutic target; novel; overexpression; prevent; protein aggregation; protein degradation; proteostasis; response; tau Proteins; tau aggregation; therapeutic development; therapeutic target; trafficking; vesicle transport; wasting

Project Summary/Abstract: Neurodegenerative diseases are among the fastest growing clinical burdens on society, and in the next 20 years Alzheimer’s Disease (AD) is projected to overtake cancer as the second leading cause of death in adults. Despite AD prevalence, there are currently no therapeutic interventions to combat the underlying pathology driving disease progression. While much is still not understood about neurodegenerative pathogenesis, the accumulation of extracellular amyloid- plaques and intracellular tau tangles are undisputed hallmarks of AD. To combat disease progression, an attractive therapeutic strategy is to investigate impairments in native proteostatic mechanisms used to dispose of this neurotoxic protein accumulation. One such mechanism which has been implicated in the development and progression of not only AD, but numerous neurodegenerative proteinopathy disorders including Parkinson’s and Huntington’s disease, is the autophagy-lysosomal network (ALN). The ALN is a bulk degradative system utilizing vesicular transport to dispose of large protein aggregates which contribute to neuronal dysfunction. This process relies on the active remodeling of the actin cytoskeleton to initiate, capture, and transport neurotoxic cargo for degradation and maintain proper proteostasis. However, mechanistically how dysregulations in cytoskeletal dynamics are associated with neurodegenerative pathology contributing to disease remains unclear. Through multiple behavioral neurodegenerative screens, we have identified an actin depolymerizing factor, cofilin, along with its upstream molecular regulators, which upon modulation improve neurodegenerative behavioral deficits and lower tau accumulation in vivo. This proposal seeks to investigate how cytoskeletal dynamics contribute to AD through genetic attenuation of the cofilin-centric cytoskeletal remodeling pathway. I hypothesize that modulating the activity of cofilin and its regulators will ameliorate AD neurodegenerative phenotypes via modification of the cytoskeleton and proteostasis. Aim 1 will utilize behavioral and histological approaches to investigate how genetic modulation of numerous genes within the remodeling pathway influence neurodegenerative phenotypes in tauopathy Drosophila and mouse models. In Aim 2, I will investigate mechanistically how this cytoskeletal remodeling pathway is involved in the formation and progression of the ALN through 1) measuring changes in neurotoxic protein accumulation upon cytoskeletal genetic modulation using various tauopathy model systems, and 2) utilizing high resolution microscopy techniques in AD patient derived induced pluripotent stem cells (iPSCs) along with biochemical in vitro assays, to investigate how genetically modulating cofilin disrupts various phases of the ALN. Upon successful completion of this project, we will identify molecular impairments of cytoskeletal remodeling associated with neurodegeneration that are involved in proteostatic imbalances and disease pathogenesis. Furthermore, we hope to identify novel therapeutic targets within this pathway capable of treating not only AD, but multiple neurodegenerative diseases caused by neurotoxic protein accumulation.

项目摘要/摘要： 神经退行性疾病是社会增长最快的临床伯恩斯（Burnens），在接下来的20年中 阿尔茨海默氏病（AD）预计将超过癌症，成为成年人的第二大死亡原因。尽管 广告流行率，目前尚无治疗干预措施来打击潜在的病理驾驶 疾病进展。虽然关于神经退行性发病机理仍然不了解很多 AD的无可争议的标志是细胞外淀粉样蛋白斑块和细胞内TAU缠结的积累。到 战斗疾病进展，一种有吸引力的理论策略是研究天然蛋白质抑制 用于处置这种神经毒性蛋白积累的机制。一种这样的机制 不仅在AD的开发和发展中实施，而且在许多神经退行性蛋白质疗法中 包括帕金森氏病和亨廷顿氏病在内的疾病是自噬 - 溶酶体网络（ALN）。 Aln 是使用囊泡转运的批量降解系统，以处理有助于的大蛋白质聚集体 到神经元功能障碍。此过程依赖于肌动蛋白细胞骨架的主动重塑来启动，捕获， 并运输神经毒性货物以降解并保持适当的蛋白质量。但是，从机械上讲如何 细胞骨架动力学的失调与有助于的神经退行性病理有关 疾病尚不清楚。通过多个行为神经退行性筛选，我们已经确定了肌动蛋白 去聚合因子Cofilin及其上游分子调节剂，随着调节的改进 神经退行性行为定义了体内tau的积累。该提议旨在调查 细胞骨架动力学如何通过以Cofilin为中心的细胞骨架的遗传衰减来促进AD 改建途径。我假设调节Cofilin及其调节剂的活性将得到改善 通过修饰细胞骨架和蛋白质的AD神经退行性表型。 AIM 1将使用 行为和组织学方法，以研究如何调节遗传基因 重塑途径影响果蝇和小鼠模型中的神经退行性表型。在 AIM 2，我将机械地研究这种细胞骨架重塑途径如何参与形成 ALN到1）测量细胞骨架上神经毒性蛋白积累的变化 使用各种tauopathy模型系统的遗传调制，以及2）使用高分辨率显微镜 AD患者衍生诱导的多能干细胞（IPSC）的技术以及生化的体外测定 为了研究一般调节Cofilin如何破坏ALN的各个阶段。成功完成 在这个项目中，我们将确定与与细胞骨架重塑相关的分子损伤 与蛋白抑制性失衡和疾病发病机理有关的神经变性。此外，我们 希望在该途径中识别能够不仅可以治疗AD，而且多重治疗的途径中的新型治疗靶标 由神经毒性蛋白积累引起的神经退行性疾病。