NURR1 EXPRESSION AND DAERGIC DYSFUNCTION RELEVANT TO PD

与 PD 相关的 NURR1 表达和 Daergic 功能障碍

• 批准号: 6598653
• 负责人: WEIDONG LE
• 金额: $ 4.52万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-25 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6598653
• 关键词: Parkinson's disease; dopamine; gene expression; laboratory mouse; methylphenyltetrahydropyridine; molecular pathology; neural degeneration; nuclear receptors

DESCRIPTION (adapted from applicant's abstract): Midbrain dopaminergic (DAergic) neuronal loss is a pathological hallmark of Parkinson's disease (PD). The cause and mechanisms underlying the loss of DAergic neurons in Parkinson's disease are poorly understood. Several lines of evidence indicate that Nurr1, a member of nuclear receptor super family, may have important role in regulating survival of DAergic neurons in Parkinson's disease. Specifically: (1) Nurr1 is highly expressed in the midbrain DAergic system. (2) Nurr1 is essential for the induction of developing midbrain DAergic neurons. (3) Nurr1 may be critical for the survival of DAergic neurons in adulthood. Reduced Nurr1 expression in adult heterozygous (Nurr1 +/-) mice or in aged wild-type mice is associated with increased vulnerability to selective DAergic neurotoxin MPTP. The applicant proposes that Nurr1 gene expression plays an important role in maintaining mature DAergic neuron function and decreased Nurr1 expression resulting from aging, genetic defects, and/or environmental factors may increase the vulnerability of DAergic dysfunction, as in Parkinson's disease. Specific Aims are proposed to investigate if Nurr1 gene is a susceptibility factor for declined DAergic function in animal models of Parkinson's disease and in patients with Parkinson's disease. Investigator will (1) delineate the association of age-related decrease in Nurr1 expression and reduction in DA levels in nigral-striatal pathway; (2) determine the vulnerability of heterozygous Nurr1-deficient mice and aged mice with reduced Nurr1 expression to MPTP; (3) evaluate the protective role of increased Nurr1 expression against DAergic neuron degeneration; and (4) determine whether Nurr1 gene expression is reduced in the brains of patients with Parkinson's disease. This proposed study will improve our understanding of the mechanism of Nurr1 gene in the selective DAergic neuron degeneration and may yield information that will help define its role in the pathogenesis of Parkinson's disease, and provide molecular basis for developing novel therapy for this devastating disease.

描述（改编自申请人的摘要）：中脑多巴胺能 （DAergic）神经元损失是帕金森病（PD）的病理标志。 帕金森病 DAergic 神经元丢失的原因和机制 对疾病了解甚少。多条证据表明 Nurr1 核受体超家族成员，可能在调节中起重要作用 帕金森病中 DAergic 神经元的存活。具体来说： (1) Nurr1 为 在中脑 DAergic 系统中高度表达。 (2) Nurr1 对于 诱导发育中脑 DAergic 神经元。 (3) Nurr1 可能至关重要 DAergic 神经元在成年期的存活。成人 Nurr1 表达减少 杂合子 (Nurr1 +/-) 小鼠或老年野生型小鼠与 增加对选择性DAergic神经毒素MPTP的脆弱性。申请人 提出 Nurr1 基因表达在维持 成熟的 DAergic 神经元功能和 Nurr1 表达降低 衰老、遗传缺陷和/或环境因素可能会增加 DAergic 功能障碍的脆弱性，如帕金森病。 提出具体目标是调查 Nurr1 基因是否易感 帕金森病动物模型中DAergic功能下降的因素 以及帕金森病患者。调查员将 (1) 描绘 年龄相关的 Nurr1 表达减少与 DA 减少的关联 黑质-纹状体通路的水平； (2) 确定脆弱性 Nurr1 杂合缺陷小鼠和 Nurr1 表达降低的老年小鼠 至 MPTP； (3)评估Nurr1表达增加对抗病毒的保护作用 DAergic 神经元变性； (4)确定Nurr1基因表达是否 帕金森病患者大脑中的细胞减少。这项拟议的研究 将提高我们对 Nurr1 基因在选择性中的机制的理解 DAergic 神经元变性，可能会产生有助于定义其变性的信息 在帕金森病发病机制中的作用，并提供分子基础 为这种毁灭性疾病开发新疗法。