MINORITY PREDOCTORAL FELLOWSHIP PROGRAM

亨廷顿病（HD）是一种进行性破坏性神经退行性疾病，其导致运动功能障碍、认知障碍和精神症状的发展。 HD的特征是基底神经元的丢失。 它是由一种叫做亨廷顿蛋白（htt）的蛋白质的突变形式引起的。 该突变是HD基因外显子1中CAG重复序列的扩增。 这种扩展，被翻译成多聚谷氨酰胺束，导致突变htt获得毒性功能的增益。 关于这种毒性功能可能是什么，已经提出了各种假设。 一种假说指出，突变htt导致了神经元存活所需的其他基因表达的中断。 已经证明htt在胚胎发生过程中是必需的，但是突变的和正常的htt在成体中的功能仍然未知。 通过使用良好建立的HD样小鼠模型（R6/2），该提议将研究减少纹状体神经元中突变htt表达的影响。 这种减少将通过递送特异性识别和切割htt mRNA的RNA切割酶（核酶）来实现。这些核酶将使用重组腺相关病毒载体（rAAV）通过立体定位注射递送到R6/2小鼠的纹状体中。 减少纹状体突变htt的表达将有助于我们阐明这种蛋白在成年小鼠纹状体的功能，并确定哪些基因，如果有的话，直接受到突变htt的抑制。 该提案还将解决将营养因子递送到R6/2小鼠脑中的治疗潜力。 从这项研究中获得的结果将提高我们对HD分子发病机制的理解，并为这种尚无治愈方法的致命疾病提供新的治疗选择。

Huntington's disease (HD) is a progressive devastating neurodegenerative disorder that results in motor dysfunction, cognitive impairment and development of psychiatric symptoms. HD is characterized by a loss of srtiatal neurons. It is caused by a mutant form of a protein termed huntingtin (htt). The mutation is an expansion of CAG repeats in exon 1 of the HD gene. This expansion, which is translated into a polyglutamine tract, causes mutant htt to acquire a gain of toxic function. Various hypotheses have been brought forward as to what this toxic function may be. One hypothesis points to a disruption, caused by mutant htt, in the expression of other genes required for neuronal survival. It has been shown that htt is required during embryogenesis but the function of both mutant and normal htt in adults remains unknown. By using a well established HD-like mouse model (R6/2) this proposal will study the effects of reducing expression of mutant htt in striatal neurons. This reduction will be achieved by delivering RNA cleaving enzymes (ribozymes) that specifically recognize and cleave the htt mRNA. These ribozymes will be delivered by stereotaxic injections using a recombinant adeno-associated viral vector (rAAV) into the striatum of R6/2 mice. Reducing striatal mutant htt expression will help us elucidate the function of this protein in adult mouse striatum and identify which genes, if any, are directly inhibited by mutant htt. This proposal will also address the therapeutic potential of delivering trophic factors into the brain of R6/2 mice. Results gained from this study will enhance our understanding of the molecular pathogenesis of HD and offer new therapeutic alternatives to a fatal disease with no known cure.