Pathophysiology of Transgenic Mouse Models of Huntington's Disease

亨廷顿病转基因小鼠模型的病理生理学

• 批准号: 8245957
• 负责人: Michael S. Levine
• 金额: $ 22.17万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8245957
• 关键词: Address; Affect; Appearance; Behavioral Symptoms; CAG repeat; Cell Communication; Cells; Cerebral cortex; Chronic; Complex; Corpus striatum structure; Development; Disease; Drug Delivery Systems; Epilepsy; Equilibrium; Etiology; Event; Functional disorder; Generations; Glutamate Receptor; Glutamates; Hereditary Malignant Neoplasm; Huntington Disease; Interneurons; Intervention; Laboratories; Lead; Membrane; Modeling; Mus; Mutation; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Outcome; Pathology; Pathway interactions; Phenotype; Play; Population; Property; Research; Role; Schizophrenia; Series; Symptoms; Synapses; Testing; Time; Transgenic Mice; Trinucleotide Repeats; age related; base; cholinergic; design; disease phenotype; hippocampal pyramidal neuron; human Huntingtin protein; mouse model; mutant; novel; prevent; receptor; receptor function; research study

DESCRIPTION (provided by applicant): The lethal mutation in Huntington's disease (HD) is an expanded trinucleotide (CAG) repeat within the huntingtin protein which ultimately causes selective neurodegeneration especially within the striatum and cortex. This proposal examines cellular mechanisms underlying functional alterations in HD. Emerging evidence indicates that dysfunctions of striatal and cortical neurons and circuits occur during the development of the disease phenotype, well before there is significant cell loss. Morphological changes in the striatum are probably primed initially by alterations in the intrinsic functional properties of striatal medium- sized spiny neurons (MSSNs), but ultimately require abnormalities in the corticostriatal glutamatergic inputs for the phenotype to be expressed. Malfunctions of the corticostriatal pathway are complex and there are multiple changes as demonstrated by significant age-related transient and more chronic interactions with the disease state. There also is growing evidence for changes in cortical microcircuits that interact to induce dysfunctions of the corticostriatal pathway. Little is known about the temporal sequence of cellular and circuit alterations, as well as the causes of selective neuronal vulnerability in striatum and cortex. We will use genetically-modified mice to address these important questions. This proposal will examine the functional interactions that occur to make specific neuronal populations more vulnerable to dysfunction and subsequent degeneration in HD. We hypothesize that the most conspicuous cellular alterations leading to dysfunction and pathology in HD result from a combination of cell-cell interactions and are not solely the outcome of cell- autonomous changes. We will test our hypothesis in three specific aims designed to: 1. Determine the electrophysiological properties that make subpopulations of striatal projection neurons and interneurons differentially vulnerable to dysfunction and degeneration in mouse models of HD, 2. Examine the alterations in the balance of excitation and inhibition in the cerebral cortex of mouse models of HD that facilitate and enable abnormalities in the striatum and 3. Examine if widespread expression of mutant huntingtin is necessary to produce differential electrophysiological alterations in identified populations of MSSNs. These studies will provide the basis for novel rational treatments of HD by delineating more restricted targets for drug intervention and also will be relevant for understanding other CAG triplet repeat diseases and neurodegenerative disorders.

描述（由申请人提供）：亨廷顿氏病（HD）中的致命突变是亨廷顿蛋白中膨胀的三核苷酸（CAG）重复，最终导致选择性神经变性，尤其是在纹状体和皮质中。该建议检查了HD功能改变的基础细胞机制。新兴的证据表明，在疾病表型的发展过程中，纹状体和皮质神经元和电路的功能障碍发生在大量细胞损失之前。纹状体中的形态变化最初可能是由于纹状体培养基刺神经元（MSSN）的内在功能特性的改变而产生的，但最终需要在皮质纹状体谷氨酸膜塔辅助输入中以表达表达表型的皮质纹状体谷氨酸膜输入的异常。皮质纹状体途径的故障是复杂的，并且存在多种变化，如年龄相关的瞬态和与疾病状态的慢性相互作用更多。还有越来越多的证据表明，相互作用的皮质微电路变化以诱导皮质纹状体途径的功能障碍。关于细胞和电路改变的时间序列以及纹状体和皮质中选择性神经元脆弱性的原因，知之甚少。我们将使用遗传改性的小鼠来解决这些重要问题。该建议将检查使特定神经元种群更容易受功能障碍和随后在HD中变性的功能相互作用。我们假设，最显着的细胞改变导致了细胞 - 细胞相互作用的组合导致HD功能障碍和病理，而不仅仅是细胞自主变化的结果。我们将在三个特定的目的中测试我们的假设：1。确定使纹状体投影神经元的亚群和神经元的亚群体的亚群体差异化，在HD的小鼠模型中差异很容易受到功能障碍和变性。 3。检查突变体亨廷顿蛋白是否需要广泛表达，以便在已识别的MSSN种群中产生差异的电生理改变。这些研究将通过描述更多受限制的药物干预靶标的新型HD合理治疗的基础，并且还与理解其他CAG三胞胎重复疾病和神经退行性疾病有关。