Mechanisms of neuronal cell death in synucleinopathies

突触核蛋白病中神经元细胞死亡的机制

• 批准号: 9088666
• 负责人: Vivek Unni
• 金额: $ 20.37万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9088666
• 关键词: Apoptosis; Autophagocytosis; Award; Biochemical; Brain; Brain Diseases; Brain imaging; Brain region; Cell Death; Cells; Cessation of life; Characteristics; Clinic; Collaborations; Data; Dementia; Disease; Doctor of Philosophy; Educational workshop; Electron Microscopy; Electrons; Foundations; Goals; Green Fluorescent Proteins; Health Sciences; Human; Image; Imaging Techniques; Independent Scientist Award; Ions; Knowledge; Lead; Lewy Body Dementia; Life; Mediating; Metabolism; Microscopic; Modeling; Molecular; Movement Disorders; Mus; Mutation; Names; Necrosis; Nerve Degeneration; Neurites; Neurodegenerative Disorders; Neurologic; Neurologist; Neurons; Nuclear; Oregon; Parkinson Disease; Parkinson' s Dementia; Parkinsonian Disorders; Pathogenesis; Pathology; Pathway interactions; Patients; Pennsylvania; Play; Preparation; Presynaptic Terminals; Process; Property; Recombinants; Recruitment Activity; Research; Role; Sampling; Scanning; Structure; System; Techniques; Testing; Toxic effect; Training; Transgenic Mice; Transgenic Organisms; Transmission Electron Microscopy; Ubiquitin; Universities; Work; alpha synuclein; brain cell; brain tissue; career; disease diagnosis; drug development; human disease; human tissue; in vivo; in vivo imaging; insight; mouse model; multicatalytic endopeptidase complex; neuron loss; neuropathology; neurophysiology; novel therapeutic intervention; presynaptic; programs; protein aggregate; public health relevance; relating to nervous system; synucleinopathy; therapy development

 DESCRIPTION (provided by applicant): Synucleinopathies are a group of clinically important, progressive neurological illnesses for which there are no approved therapies that can slow, halt or reverse progression. These diseases are defined by the presence of abnormal aggregates of the protein α-synuclein within neurites and cell bodies, known as Lewy pathology. Lewy inclusions are found in brain regions where cell death occurs, but it is not clear how they relate to disease. Recent preliminary data in mouse models using sophisticated, new in vivo imaging approaches suggests that Lewy pathology forms out of the neuron's endogenous α-synuclein after seeding with recombinant produced α-synuclein fibrils. Furthermore, only neurons that develop Lewy inclusions are fated to die in these models. Critical questions remain, however, including whether human Lewy pathology is formed by similar mechanisms and if human neurons also die by similar pathways as those in fibril-seeded mouse models. In order to answer these questions, advanced electron microscopic (EM) approaches will be used. The long-term goal is to determine how Lewy inclusion-bearing cells degenerate in human disease in order to guide the development of therapies to halt this process. This proposal will test the central hypothesis that specific structural and molecular properties of Lewy inclusions drive associated neuronal cell death in fibril- seeded mouse models and humans with Parkinsonism. This will be tested in three specific aims: 1) Determine the Lewy inclusion structural & molecular characteristics that predict cell death. 2) Determine the mode of programmed cell death in Lewy inclusion-bearing neurons. 3) Test whether alteration of Lewy inclusion properties underlies aggressive forms of neurodegeneration. The proposed study will be conducted at Oregon Health & Science University in collaboration with consultants at the Mayo Clinic and the University of Pennsylvania, each with complementary expertise in EM approaches to study brain disease and the neuropathology of Parkinsonism. This K02 - Independent Scientist Award will provide the candidate with the expertise in advanced EM approaches needed to study this relationship of Lewy pathology to neurodegeneration. It will also involve a variety of structured coursework, workshops and formal advising programs in order to provide an excellent foundation for launching an independent research career. Ultimately, the knowledge gained has the potential to lead to new therapeutic strategies that target cell death in ways that treat Parkinson's disease, Dementia with Lewy Bodies and related disorders.

 描述（由申请人提供）：突触核蛋白病是一组临床重要的进行性神经系统疾病，目前尚无获批的治疗方法可以减缓、停止或逆转进展。这些疾病的定义是在神经突和细胞体内存在蛋白质α-突触核蛋白的异常聚集体，称为Lewy病理学。路易包涵体存在于细胞死亡的大脑区域，但尚不清楚它们与疾病的关系。最近使用复杂的、新的体内成像方法的小鼠模型的初步数据表明，在接种重组产生的α-突触核蛋白原纤维后，路易病理学由神经元的内源性α-突触核蛋白形成。此外，在这些模型中，只有发展Lewy包涵体的神经元注定会死亡。然而，关键问题仍然存在，包括人类路易病理学是否由类似的机制形成，以及人类神经元是否也通过与原纤维接种小鼠模型相似的途径死亡。为了回答这些问题，将使用先进的电子显微镜（EM）方法。长期目标是确定携带Lewy包涵体的细胞如何在人类疾病中退化，以指导治疗方法的开发来阻止这一过程。该提案将测试中心假设，即路易包涵体的特定结构和分子特性驱动原纤维接种小鼠模型和帕金森症患者中的相关神经元细胞死亡。这将在三个具体目标中进行测试：1）确定预测细胞死亡的Lewy包涵体结构和分子特征。2)确定路易包涵体神经元中程序性细胞死亡的模式。3)测试Lewy包涵体性质的改变是否是神经变性侵袭性形式的基础。拟议的研究将在俄勒冈州健康与科学大学与马约诊所和宾夕法尼亚大学的顾问合作进行，每个人都有EM方法研究脑部疾病和帕金森症神经病理学的互补专业知识。这个K 02-独立科学家奖将为候选人提供研究路易病理学与神经退行性疾病之间关系所需的先进EM方法的专业知识。它还将涉及各种结构化的课程，研讨会和正式的咨询计划，以便为开展独立的研究生涯提供良好的基础。最终，所获得的知识有可能导致新的治疗策略，以治疗帕金森病，路易体痴呆症和相关疾病的方式靶向细胞死亡。