Genetic Models to Probe the Role of Complex-1 Dysfunction in Neurologic Disease

探索 Complex-1 功能障碍在神经系统疾病中作用的遗传模型

• 批准号: 7870069
• 负责人: Matthew J Lavoie
• 金额: $ 21.08万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-15 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7870069
• 关键词: Affect; Animal Model; Attention; Biology; Brain region; Cell Culture Techniques; Characteristics; Complex; Data; Deposition; Development; Disease; Event; Functional disorder; Generations; Genes; Genetic; Genetic Models; Goals; Human; In Vitro; Lesion; Life; Maps; Membrane; Mitochondria; Modeling; Molecular; Molecular Chaperones; Mus; Neurologic; Neurons; Parkinson Disease; Parkinsonian Disorders; Play; Population; Prevention; Process; Property; Proteins; Reporting; Research Proposals; Rodent; Role; Substantia nigra structure; Therapeutic; Toxin; Validation; Work; alpha synuclein; base; chemical addition; combat; design; embryonic stem cell; inhibitor/antagonist; interest; mitochondrial dysfunction; mouse model; nonhuman primate; novel; novel therapeutics; premature; public health relevance; synuclein

DESCRIPTION (provided by applicant): Perhaps the greatest obstacle in the development of disease-modifying therapeutics to combat or cure Parkinson's disease (PD) is the lack of predictive animal models. While familial forms of PD have guided the current generation of mouse models, they have thus far failed to recapitulate essential features of the human condition. Most notably lacking from these models is the spontaneous degeneration of the substantia nigra, and the accumulation of a-synuclein in non-synuclein based mice. Given the undeniable need for vertebrate models for target identification and validation in the translational arena, new models must be considered. We have focused our attention toward aspects of idiopathic PD in our rational design of a novel mouse model of this disease. Deficiencies in mitochondrial Complex-1 are routinely reported in idiopathic PD. In addition, chemical inhibitors of Complex-1 reproduce the characteristic selective lesion of the substantia nigra, deposition of the a-synuclein protein, and subsequent parkinsonism in rodents and non-human primates. There is even a small population of humans who ingested a Complex-1 toxin and subsequently presented clinically with an L-DOPA responsive parkinsonism. Numerous genetic studies have likewise implicated familial PD genes in mitochondrial biology, further heightening our interest in the role that mitochondrial dysfunction plays as a primary event in PD. We propose to characterize a novel model of PD by genetically targeting Complex-1 function. Complex-1 is a large integral membrane complex comprised of over 45 subunits whose assembly is aided by several proprietary chaperones. A critical question is which of these ~50 genes would be the most suitable target for a model of PD. We have focused on a Complex-1 gene that, when deficient in humans, results in severe degeneration of the substantia nigra, the same brain region affected in all PD cases. These data strongly suggest this gene to be an ideal target for the generation of an idiopathic PD animal model. The goal of this exploratory research proposal is to examine the downstream molecular consequences of Compex-1 dysfunction in vitro and characterize the basic neuropathological properties of Complex-1 deficiency in a novel genetic mouse model of PD. This work will determine the suitability of our model for further basic and translational efforts to understand and treat the PD disease process. PUBLIC HEALTH RELEVANCE: A major obstacle in the generation of new therapeutics for the treatment or prevention of Parkinson's disease is the lack of suitable animal models of spontaneous, premature nigral degeneration accompanied by other classic features of idiopathic Parkinson's disease. Here we will examine the suitability of a novel genetic model of Parkinson's disease in neuronal cell culture and in mice in an effort to satisfy perhaps the greatest unmet need in the field.

描述（由申请人提供）：也许开发对抗或治愈帕金森病（PD）的疾病修饰疗法的最大障碍是缺乏预测性动物模型。虽然PD的家族形式指导了当前一代的小鼠模型，但它们迄今未能概括人类状况的基本特征。这些模型中最明显缺乏的是黑质的自发变性，以及基于非突触核蛋白的小鼠中α-突触核蛋白的积累。鉴于在翻译竞技场中对脊椎动物模型用于目标识别和验证的不可否认的需求，必须考虑新的模型。我们已经把我们的注意力集中到特发性PD方面，在我们的合理设计的一种新的小鼠模型，这种疾病。线粒体复合物-1的缺陷通常在特发性PD中报告。此外，复合物-1的化学抑制剂在啮齿动物和非人灵长类动物中再现黑质的特征性选择性损伤、α-突触核蛋白的沉积以及随后的帕金森症。甚至有一小部分人摄入了复合物-1毒素，随后在临床上表现为L-DOPA反应性帕金森综合征。许多遗传学研究同样涉及线粒体生物学中的家族性PD基因，进一步提高了我们对线粒体功能障碍作为PD主要事件的作用的兴趣。我们建议通过基因靶向复合物-1功能来表征PD的新模型。复合物-1是由超过45个亚基组成的大型完整膜复合物，其组装由几种专有的分子伴侣辅助。一个关键的问题是这50个基因中的哪一个将是PD模型的最合适的靶标。我们专注于一个复合物-1基因，当人类缺乏时，会导致黑质严重退化，这是所有PD病例中受影响的同一大脑区域。这些数据强烈表明该基因是产生特发性PD动物模型的理想靶标。这项探索性研究计划的目标是在体外研究Compex-1功能障碍的下游分子后果，并在一种新的遗传性PD小鼠模型中表征Complex-1缺陷的基本神经病理学特性。这项工作将确定我们的模型是否适合进一步的基础和翻译工作，以了解和治疗PD疾病的过程。 公共卫生关系：产生用于治疗或预防帕金森病的新疗法的主要障碍是缺乏伴有特发性帕金森病的其他经典特征的自发性过早黑质变性的合适动物模型。在这里，我们将研究一种新的帕金森病遗传模型在神经元细胞培养和小鼠中的适用性，以满足该领域可能最大的未满足的需求。