Establishment of a transgenic monkey of Huntingtons's diesease

描述(由申请人提供)：非人灵长类动物(NHP；猴子)在许多生物医学研究领域做出了重大贡献，因为它们是研究人类疾病的宝贵模型。最近转基因技术的进步导致了第一个亨廷顿病转基因猴子模型的创建。转基因HD猴子会出现与人类患者相似的神经病理，这在啮齿动物模型中很少观察到。除了突变的亨廷顿蛋白(HTT)对猴子的神经毒性外，HD猴子还会出现类似HD患者的不自主运动和协调身体运动的困难。我们已经成功地实现了最初应用的目标，开发了一种表达突变HTT并出现与人类患者相似的症状的转基因HD猴子。我们共培育了5只足月出生的转基因猴子，它们都是双转基因的，携带突变的HTT和绿色荧光蛋白基因。其中三名患有HD的猴子婴儿表现出严重的舞蹈症和肌张力障碍。两只存活了一天，第三只存活了一个月。临床症状和疾病严重程度的变化提示CAG重复次数、整合事件的数目和HTT片段的大小的影响。我们的目标是继续描述现有的两只高清猴子，目前已有10个月大，以及预计在父母申请的最后一年预算中的新一代高清猴子。因此，HD Money创始人队伍将会建立起来。这项应用旨在继续监测HD猴子队列中的疾病发展，并通过非侵入性成像和认知行为测试监测HD进展。这个应用程序的主要目标是对HD猴子进行深入的表征，并建立一个具有已知基因和表型的HD猴子队列。我们将评估猴子模型是否比啮齿动物模型更能概括人类的HD。我们还制定了一项计划，建立一个房屋署猴子种群，供房屋署研究界使用。我们的三个具体目标是：(1)评价转基因HD猴的表型特征；(2)评价转基因HD猴的分子和细胞特性；(3)HD猴精子和胚胎的冷冻保存。相关性(参见说明)：这项研究将继续描述转基因HD猴子的特征，并确定与其他动物模型相比，转基因猴子模型是否具有模拟人类遗传性神经退行性疾病的特权。此外，房署亦制定了一套策略性计划，以设立一批房屋署猴子，供房署研究界参考。

DESCRIPTION (provided by applicant): Nonhuman primates (NHPs; monkeys) have contributed significantly in many areas of biomedical research as they are invaluable models for studying human diseases. Recent advancements in transgenic technology have resulted in the creation of the first transgenic monkey model of Huntington's disease (HD). Transgenic HD monkeys develop neuropathologies similar to that of human patients, which are rarely observed in rodent models. Besides the neurotoxicity of mutant huntingtin (htt) in monkeys, HD monkeys also develop involuntary movement and difficulties in coordinating body movement similar to that of HD patients. We have successfully accomplished our goal of the original application in developing a transgenic HD monkey that expresses mutant htt and develops symptoms comparable to human patients. We have generated a total of five transgenic monkeys that were born at full term and they were all double transgenic with mutant htt and green fluorescent protein genes. Three of the HD monkey infants exhibited severe signs of chorea and dystonia. Two survived for one day and the third for one month. The variations in their clinical symptoms and the severity of the disease suggest the effect of the number of CAG repeats, the number of integration events, and the size of the htt fragment. Our objective is to continue characterizing the two existing HD monkeys, currently ten months old, and the new generation of HD monkeys that are expected in the last budgeted year of the parent application. Thus a cohort of HD monkey founders will be established. This application aims to continue monitoring disease development among the cohort of HD monkeys and monitoring HD progression by non-invasive imaging and cognitive behavioral tests. The primary goals of this application are to perform in-depth characterization on HD monkeys and establish a cohort of HD monkeys with known genotypes and phenotypes. We will evaluate if the HD monkey model is a better model to recapitulate HD in humans than a rodent model. We have also laid out a plan for establishing a cohort of HD monkeys, which will be available for the HD research community. Our three specific aims are: (1) Assessment of phenotypic characteristics in transgenic HD monkeys, (2) Assessment of molecular and cellular characteristics in transgenic HD monkeys, and (3) Cryopreservation of HD monkey's spermatozoa and embryos. RELEVANCE (See instructions): This study is to continue characterizing transgenic HD monkeys and determines if a transgenic monkey model has privileged of modeling human inherited neurodegenerative diseases compared to the other animal models. A strategic plan is also developed for the establishment of a cohort of the HD monkey, which will be available for the HD research community.