Cortical Mechanisms in Lewy Body Dementia

路易体痴呆的皮质机制

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目概要/摘要路易体痴呆是退行性痴呆的一种常见形式，这些疾病使人衰弱，导致身体衰弱。幻视、意识波动、睡眠不安、跌倒和抑郁，所有这些都会导致丧失意识在这些疾病中，α-突触核蛋白会影响独立性、残疾和重大的护理负担。累积成特征性的“路易体”和“路易体痴呆”。弥漫性细胞内皮质路易体、皮质变薄以及神经元解剖结构（包括树突）的丧失这些变化可能是由于 α-突触核蛋白寡聚物引起的钙调节改变而发生的，在病理条件下积累的α-突触核蛋白在人类中会导致家族性遗传。疾病，包括痴呆症，因此提供了一个有用的模型来评估神经机制该提案利用小鼠皮质中α-突触核蛋白的病毒过度表达来检查功能障碍。具体而言，该提议首先提出了随着蛋白质积累而在皮质神经元中发生的病理变化。检验以下假设：局部 α-突触核蛋白积累会导致树突棘不稳定，从而导致这是使用纵向活体动物 2 光子成像反复测试的树突棘损失。其次，随着病理的发展观察单个树突棘，该建议评估钙是否存在。由于α-突触核蛋白积累，动力学随时间变化，这是网络的潜在机制该提案的研究结果将证明α-突触核蛋白如何发挥作用。其在皮质细胞中的病理作用并评估基于 Ca2+ 动力学的机制模型。随着时间的推移进行评估，这些研究更有可能模拟人类疾病的各个方面并产生可转化的结果作为职业发展补助金，该提案非常理想；它利用了申请人过去的技能：2- 使用 Ca2+ 通过补充、机械和计算方法进行树突棘光子成像成像，这对申请人来说是新颖的，该机构致力于提供支持和资源。申请人的成功所必需的，在所提议的研究领域有强有力的指导，辅之以顾问指导和正式研讨会，这将提供关键培训。将促进申请人作为学术医师科学家的职业生涯的机会，重点关注了解和治疗路易体痴呆症。