Cortical Mechanisms in Lewy Body Dementia

路易体痴呆的皮质机制

• 批准号: 10188658
• 负责人: Georgina Aldridge
• 金额: $ 18.82万
• 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/10188658
• 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; Dementia with Lewy Bodies; 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 路易体痴呆是退化性痴呆的常见形式。这些疾病令人衰弱，导致 视觉幻觉，意识波动，睡眠不安，跌倒和沮丧，都导致失去 独立，残疾和重大照顾者负担。在这些疾病中，蛋白质α-核蛋白 积累到病理学的“路易尸体”和“路易神经病”中。 Lewy身体痴呆患者患有 弥漫性细胞内皮质刘易体，皮质稀疏和神经元解剖学的丧失，包括树突 和刺。这些变化可能是由于α-突触核蛋白低聚物引起的钙调节的改变，即 在病理条件下积累。人类α-核蛋白的过表达导致家庭 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。该建议使用小鼠皮质中α-核蛋白的病毒过表达来检查 随着蛋白质的积累，皮质神经元中发生的病理变化。具体而言，该提议首先 检验了以下假设：局部α-核蛋白积累会诱导树突状脊柱不稳定性，导致 树突状的脊柱损失加班。使用纵向，活动物，2光片成像进行测试，以反复 将单个树突状刺视为病理发展。其次，该提案评估是否钙 动力学随着时间的推移而变化，这是由于α-突触核蛋白的积累，这是网络的潜在机制 功能障碍和解剖病理学。该提案中的发现将证明A-核蛋白如何执行 它在皮质细胞中的病理作用，并根据CA2+动力学评估机械模型。通过包括 随着时间的流逝，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。作为职业发展赠款，这一建议是理想的选择。它利用申请人的过去技能2-- 使用Ca2+的完整，机械和计算方法对树突状刺的光子成像 成像，对申请人来说是新颖的。该机构致力于提供支持和资源 申请人成功所必需的。提议的研究领域有很强的精神验证 补充顾问和正式研讨会的指示。一起，这将提供关键培训 将推进申请人作为学术身体科学家的职业的机会，专注于 了解和治疗路易的身体痴呆症。