Cortical Mechanisms in Lewy Body Dementia

路易体痴呆的皮质机制

• 批准号: 9976607
• 负责人: Georgina Aldridge
• 金额: $ 18.72万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-18 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9976607
• 关键词: Affect; Age; Anatomy; Animals; Applications Grants; Area; Axon; Brain Diseases; Brain Stem; Calcium; Caregiver Burden; Cells; Cephalic; Characteristics; Computer Analysis; Conscious; Data; Dementia; Dendrites; Dendritic Spines; Deposition; Development; Diffuse; Disease; Educational workshop; Evaluation; Familial disease; Functional disorder; Hallucinations; Homeostasis; Human; Image; Incidence; Individual; Injections; Institution; Instruction; K-Series Research Career Programs; Knowledge; Lead; Lewy Bodies; Lewy Body Dementia; Lewy Body Disease; Lewy neurites; Link; Literature; Measures; Mediating; Mental Depression; Mentors; Mentorship; Modeling; Monitor; Mus; N-Methylaspartate; NMDA receptor antagonist; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Parkinson' s Dementia; Pathologic; Pathologic Processes; Pathology; Patients; Physicians; Population; Prefrontal Cortex; Prevalence; Property; Proteins; Regulation; Research; Resources; Role; Scientist; Secondary to; Sleep disturbances; Societies; Structure; Synapses; Techniques; Testing; Thinness; Time; Training; Vertebral column; Viral; Visual Hallucination; Work; alpha synuclein; awake; base; career; career development; cranium; density; disability; experience; falls; human disease; in vivo; in vivo calcium imaging; insight; network dysfunction; neuron loss; neuronal circuitry; novel; overexpression; protein function; serial imaging; skills; sleep abnormalities; success; training opportunity; two photon microscopy; two-photon

Project Summary/Abstract Lewy Body dementias are a common form of degenerative dementia. These diseases are debilitating, causing visual hallucinations, fluctuations in consciousness, disturbed sleep, falls, and depression, all leading to loss of independence, disability and significant caregiver burden. In these disorders, the protein alpha-synuclein accumulates into pathognomonic “Lewy bodies” and “Lewy neurites”. Patients with Lewy Body dementia have diffuse intracellular cortical Lewy Bodies, cortical thinning, and loss of neuronal anatomy, including dendrites and spines. These changes may occur due to altered calcium regulation caused by alpha-synuclein oligomers, which accumulate under pathologic conditions. Overexpression of alpha-synuclein in humans leads to familial disease, including dementia, and therefore provides a useful model to evaluate the mechanisms of neuronal dysfunction. This proposal uses viral overexpression of alpha-synuclein in the cortex of mice to examine the pathological changes occurring in cortical neurons as the protein accumulates. Specifically, this proposal first tests the hypothesis that local alpha-synuclein accumulation induces dendritic spine instability, leading to dendritic spine loss overtime. This is tested using longitudinal, live animal, 2-photon imaging to repeatedly observe individual dendritic spines as pathology develops. Secondly, this proposal evaluates if calcium dynamics change over time due to alpha-synuclein accumulation, a potential mechanism for network dysfunction and anatomical pathology. The findings from this proposal will demonstrate how a-synuclein exerts its pathological effect in cortical cells and evaluate a mechanistic model based on Ca2+ dynamics. By including evaluation over time, these studies are more likely to model aspects of human disease and lead to translatable treatments. As a career development grant this proposal is ideal; it leverages the applicant’s past skills in 2- photon imaging of dendritic spines with a complementary, mechanistic and computational approach using Ca2+ imaging, which is novel to the applicant. The institution is dedicated to providing the support and resources necessary for the applicant’s success. There is strong mentorship available in areas of research proposed, supplemented with instruction by consultants and formal workshops. Together, this will provide key training opportunities that will advance the applicant’s career as an academic physician-scientist focusing on understanding and treating Lewy Body Dementias.

项目摘要/摘要 路易体痴呆是退行性痴呆的一种常见形式。这些疾病使人虚弱，导致 视觉幻觉、意识波动、睡眠障碍、跌倒和抑郁，所有这些都会导致失眠 独立、残疾和沉重的照顾者负担。在这些疾病中，α-突触核蛋白 积聚成致病的“路易小体”和“路易神经突起”。路易体痴呆患者有 弥漫性细胞内皮质路易小体，皮质变薄，神经元解剖丢失，包括树突 还有脊椎。这些变化可能是由于α-突触核蛋白寡聚体引起的钙调节改变而发生的， 在病理条件下堆积。α-突触核蛋白在人类中的过度表达导致家族性 疾病，包括痴呆，因此提供了一个有用的模型来评估神经元的机制 功能障碍。这一建议利用小鼠大脑皮质中α-突触核蛋白的病毒过度表达来检查 当蛋白质积累时，皮质神经元中发生的病理变化。具体地说，这项建议首先 验证了局部α-突触核蛋白积聚导致树突棘不稳定的假设，导致 树突状脊椎超时丢失。这是使用纵向、活体动物、双光子成像来反复测试的 随着病理学的发展，观察单个树突棘。其次，这项建议评估是否有钙 网络的一种潜在机制--α-突触核蛋白积聚导致的动态变化 功能障碍和解剖病理学。这个提案的发现将展示a-突触核蛋白是如何发挥作用的。 它在大脑皮层细胞中的病理效应，并评估一个基于钙动力学的机制模型。通过包括 随着时间的推移，这些研究更有可能模拟人类疾病的各个方面，并导致可翻译 治疗。作为一项职业发展资助，这项建议是理想的；它利用了申请者过去的技能，在2- 使用钙离子的互补、机械和计算方法的树突棘的光子成像 成像，这对申请者来说是新的。该机构致力于提供支持和资源 对于申请者的成功来说是必要的。在建议的研究领域有强大的指导， 辅以顾问和正式讲习班的指导。总而言之，这将提供关键的培训 机会将促进申请人的职业生涯，作为一名学术内科医生-科学家，专注于 对路易体痴呆的认识和治疗。