FUNCTIONAL NEUROANATOMY OF MOVEMENT DISORDERS

运动障碍的功能神经解剖学

• 批准号: 6543369
• 负责人: LUCY L BROWN
• 金额: $ 26.8万
• 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/6543369
• 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）：虽然亨廷顿病（HD）的基因已被鉴定，但导致细胞病理和变性的过程仍不清楚。拟议的研究检查了两种亨廷顿病转基因小鼠模型的早期病理学和病理生理学。我们在一种突变模型（可逆HD94模型）中的初步数据表明，纹状体的化学结构在疾病的早期症状阶段发生了改变：突变体中富含μ阿片受体的纹状体比对照组更多，这可能导致纹状体和基质区室之间的活性失衡，并产生舞蹈症和不自主活动的症状。研究将通过使用免疫细胞化学方法鉴定纹状体来确定突变体中是否存在更多纹状体。工作假设指出，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一个关键部分是产前和产后的异常神经发生，并且突变体中纹状体的数量反映了神经发生异常。此外，我们的纹状体行为功能模型预测突变体将对多巴胺激动剂更加敏感。最后，研究将通过使用胸苷类似物溴脱氧尿苷（BrdU）来研究突变体及其对照的产前和成体细胞增殖和神经发生。这些研究可能为亨廷顿基因的功能提供线索，并确定治疗策略的目标。此外，这些研究还涉及成人大脑的可塑性和增殖能力。