Role of GDNF, ER stress and mitochondrial function in effects of acupuncture in models of parkinsonism

GDNF、ER应激和线粒体功能在针刺帕金森病模型中的作用

• 批准号: 8912366
• 负责人: Barry J Hoffer
• 金额: $ 18.92万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8912366
• 关键词: Acupuncture Therapy; Acute; Alternative Therapies; Apoptotic; Asia; Attention; Axon; Behavior; Behavioral; Biochemical; Brain-Derived Neurotrophic Factor; Capital; China; Chinese Traditional Medicine; Clinical; Collaborations; Corpus striatum structure; Data; Dendrites; Disease; Dopamine; Dyskinetic syndrome; Electroacupuncture; Frequencies; GDNF gene; Gene Expression; Gene Targeting; Genes; Genetic; Health; Heat shock proteins; India; Injury; Institution; Intervention; Lesion; Mediating; Medical; Medicine; Methods; Microglia; Midbrain structure; Mitochondria; Mitochondrial Proteins; Modeling; Mus; Neurons; Neurotoxins; Parkinson Disease; Parkinsonian Disorders; Patients; Pharmacologic Substance; Placebos; Predisposition; Production; Proteins; Qi; Research; Role; Site; Substance P; Substantia nigra structure; Symptoms; Time; Tissues; Toxin; Universities; Up-Regulation; angiogenesis; base; design; dopaminergic neuron; endoplasmic reticulum stress; experience; indexing; mitochondrial dysfunction; motor deficit; mutant; neuroprotection; neurotrophic factor; novel strategies; programs; progressive neurodegeneration; protein misfolding; research study; response; stress protein; success

DESCRIPTION (provided by applicant): Traditional Chinese Medicine (TCM) may provide some novel approaches to Parkinson's Disease treatment that deserve further attention by Western medicine. A prime example is electroacupuncture, a well-known type of TCM that has been used as an alternative therapy in patients with PD with some success. We propose to establish a collaboration among three institutions, Case Western Reserve University (CWRU), the University of Pittsburgh (Pitt), and China Medical University (CMU), to initiate a research program on acupuncture as an intervention for PD. General hypothesis: EA reduces the vulnerability of DA neurons to both environmental and genetic factors by activating gene expression for neurotrophic factors (NTFs) including GDNF, which then reduces the susceptibility of these neurons to ER stress and mitochondrial dysfunction. This R21 has three specific aims. Aim 1: To establish in our U.S. labs a well-characterized model of EA neuroprotection in MPTP-treated mice. In the first experiment we will use C57/b16 mice and a progressive MPTP model. Six groups will be involved: (1) acute MPTP plus 100 Hz EA, (2) MPTP plus 0 Hz acupuncture, (3) MPTP plus EA at a non-effective site, (4) MPTP treatment alone, (5) vehicle-treated mice given EA, and (6) vehicle treated mice plus sham acupuncture. Behavioral, histological and biochemical analysis will be used to assess neuroprotection after 2.5 and 5.5 weeks. Aim 2: To determine the influence of EA on indices of ER stress and mitochondrial function. Using tissue generated in Experiments 1 and 2, we will assess activation of downstream targets of ER stress, protein upregulation of UPR target genes and mitochondrial parameters using biochemical and immunohistochemical methods. Aim 3: To determine if there is an interaction between GDNF availability on the response to EA. Two different groups of GDNF null mutants will be treated acutely with MPTP, subjected to EA or sham treatments, and then EA-induced neuroprotection assessed.

描述（申请人提供）：中医可能为帕金森病的治疗提供一些新的方法，值得西医进一步关注。一个典型的例子是电针，这是一种众所周知的中医疗法，已被用作帕金森病患者的替代疗法，并取得了一些成功。我们建议凯斯西储大学 (CWRU)、匹兹堡大学 (Pitt) 和中国医科大学 (CMU) 这三个机构之间建立合作，启动针灸干预 PD 的研究项目。一般假设：EA 通过激活包括 GDNF 在内的神经营养因子 (NTF) 的基因表达，降低 DA 神经元对环境和遗传因素的脆弱性，从而降低这些神经元对 ER 应激和线粒体功能障碍的易感性。 R21 有三个具体目标。目标 1：在我们的美国实验室中建立一个经过 MPTP 处理的小鼠中特征良好的 EA 神经保护模型。在第一个实验中，我们将使用 C57/b16 小鼠和渐进式 MPTP 模型。将涉及六个组：(1) 急性 MPTP 加 100 Hz EA，(2) MPTP 加 0 Hz 针灸，(3) MPTP 加无效部位的 EA，(4) 仅 MPTP 治疗，(5) 载体治疗给予 EA 治疗的小鼠，以及 (6) 媒介物治疗的小鼠加假针灸。 2.5 周和 5.5 周后将使用行为、组织学和生化分析来评估神经保护作用。目标 2：确定 EA 对 ER 应激和线粒体功能指标的影响。使用实验 1 和 2 中生成的组织，我们将使用生化和免疫组织化学方法评估 ER 应激下游靶点的激活、UPR 靶基因的蛋白质上调和线粒体参数。目标 3：确定 GDNF 可用性与 EA 响应之间是否存在交互作用。将用 MPTP 急性治疗两组不同的 GDNF 无效突变体，进行 EA 或假治疗，然后评估 EA 诱导的神经保护作用。