Molecular Mechanisms of Neurodegeneration

这项研究的长期目标是定义和表征蛋白质突变导致神经退行性疾病的分子机制，并确定改善神经细胞中未折叠蛋白质中间体积累引起的疾病症状的药理学药物。未折叠蛋白质在细胞内区室中的积累是 被认为是许多神经退行性疾病，包括ALS、帕金森、亨廷顿和阿尔茨海默病的发病机制的基础。最近，未折叠蛋白反应也与代谢综合征（糖尿病/肥胖/胰岛素抵抗/心血管疾病）的病理生理学有关，这显著增加了我们工作的影响，因为未折叠疾病可能与超过6%的美国人有关。我们的两个关键组成部分 研究的重点是用于基因操作（如基因切除或引入异源转基因）的明确定义的小鼠模型的可用性，以及未折叠蛋白质疾病患者参与临床研究的意愿。在此应用中，我们将继续与患者合作，测量MRI的几个临床指标，并将其与疾病严重程度相关联。此外，我们将产生一种新的未折叠蛋白质疾病的小鼠模型，这将使我们能够扩展我们对未折叠蛋白质疾病的病理生理学的理解。具体目标#1：我们将开发一种新的体内小鼠模型，其中未折叠的蛋白质反应可以被 真实的时间，在单个细胞中，在体内。该模型将使我们能够识别UPR诱导的转录因子的新基因靶点。目前，已经确定了几个目标，从体外培养的细胞，但是，我们发现，在体内实验的数据往往在体外研究相矛盾。我们的范式将使我们能够描述事件的时间序列， 与少突胶质细胞中蛋白质运输缺陷相关的神经变性的病理生理学。

The long term goals of this research are to define and characterize molecular mechanisms by which mutations in proteins cause neurodegenerative disease and to identify pharmacological agents that ameliorate disease symptoms stemming from the accumulation of unfolded protein intermediates in neural cells. The accumulation of unfolded proteins in intracellular compartments is thought to underlie pathogenesis for a number of neurodegenerative diseases, including ALS, Parkinson, Huntington and Alzheimer diseases. More recently, the unfolded protein response has also been implicated in the pathophysiology of metabolic syndrome (diabetes/obesity/insulin resistance/cardiovascular disease), which significantly increases the impact of our work because unfolded diseases may be relevant to more than 6% of Americans. Two key components of our research have been the availability of well-defined mouse models for genetic manipulation, such as gene ablation or the introduction of heterologous transgenes, and the willingness of patients with unfolded protein disease to be involved in clinical studies. In this application, we will continue our work with patients to measure several clinical metrics from MRI and correlate these with disease severity. In addition, we will generate a novel mouse model on unfolded protein disease that will allow us to extend our understanding of the pathophysiology of unfolded protein disease. Specific Aim#1: we will develop a novel in vivo mouse model in which the unfolded protein response can be followed in real time, in individual cells, in vivo. This model will allow us to identify novel gene targets of UPR-induced transcription factors. Currently, several targets have been identified from in vitro cells in culture; however, we find that the data from in vivo experiments often contradict in vitro studies. Our paradigm will enable us to characterize the temporal sequence of events that generate the pathophysiology of neurodegeneration associated with protein trafficking defects in oligodendrocytes.