FUNCTIONAL NEUROANATOMY OF MOVEMENT DISORDERS

运动障碍的功能神经解剖学

• 批准号: 6609665
• 负责人: LUCY L BROWN
• 金额: $ 23.8万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6609665
• 关键词: Huntington's disease; abnormal involuntary movement; behavior test; cell differentiation; cell proliferation; corpus striatum; developmental disease /disorder; disease /disorder model; dopamine agonists; drug screening /evaluation; gene expression; gene mutation; genetic disorder; genetic regulation; genetically modified animals; glia; immunocytochemistry; laboratory mouse; neural degeneration; neural plasticity; neurogenesis; neurons; neuropathology; nonhuman therapy evaluation; opioid receptor

DESCRIPTION (provided by applicant): Although the gene for Huntington's disease (HD) has been identified, the processes that lead to cell pathology and degeneration are still unclear. The proposed studies examine early pathology and pathophysiology in two transgenic mouse models of Huntington's disease. Our preliminary data in one mutant model, the reversible HD94 model, suggest that the chemoarchitecture of the striatum is altered in early symptomatic stages of the disease: there are more mu opioid receptor-rich striosomes in mutants than in controls, which may lead to an imbalance of activity between the striosome and matrix compartments and produce the symptoms of chorea and involuntary activity. The studies will determine whether there are more striosomes in mutants by using immunocytochemical methods to identify striosomes. The working hypothesis states that the early stages of the disease are associated with abnormal developmental processes. The specific hypothesis is that a critical part of the pathology underlying the symptoms and final degenerative process of Huntington's disease is abnormal neurogenesis prenatally and postnatally, and that the number of striosomes in mutants reflects neurogenesis abnormalities. In addition, our model of the behavioral functions of striosomes predicts that mutants will be more sensitive to dopamine agonists. Finally, the studies will investigate prenatal and adult cell proliferation and neurogenesis in mutants and their controls by using a thymidine analogue, bromodeoxyuridine (BrdU). The studies may provide clues to the function of the gene huntingtin, and define a target for therapeutic strategies. In addition, these studies address the plastic and proliferative capacity of the adult brain.

描述（由申请人提供）：虽然已经鉴定出了亨廷顿病（HD）的基因，但导致细胞病理和变性的过程仍不清楚。该研究计划在两个亨廷顿病转基因小鼠模型中检测早期病理学和病理生理学。我们的初步数据在一个突变体模型，可逆的HD94模型，表明纹状体的化学结构改变在早期症状阶段的疾病：有更多的μ阿片受体丰富的纹状体突变体比对照组，这可能会导致之间的活动不平衡的纹状体和基质室，并产生舞蹈病和不自主活动的症状。本研究将通过免疫细胞化学方法鉴定纹状体，以确定突变体中是否存在更多的纹状体。工作假说指出，疾病的早期阶段与异常的发育过程有关。具体的假设是，亨廷顿病的症状和最终退化过程的病理学的关键部分是产前和产后异常的神经发生，并且突变体中的纹状体数量反映了神经发生异常。此外，我们的模型的行为功能的纹状体预测，突变体将更敏感的多巴胺激动剂。最后，研究将调查产前和成人细胞增殖和神经发生的突变体和他们的控制，通过使用胸苷类似物，溴脱氧尿苷（BrdU）。这些研究可能为亨廷顿基因的功能提供线索，并为治疗策略确定目标。此外，这些研究还涉及成人大脑的可塑性和增殖能力。