Mechanisms of Exercise-Induced Protection and Rescue in Models of Dopamine Loss

多巴胺丢失模型中运动诱导的保护和救援机制

• 批准号: 8716820
• 负责人: Barry J Hoffer
• 金额: $ 57.61万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8716820
• 关键词: Activities of Daily Living; Affect; Animal Model; Animals; Apoptosis; Astrocytes; Behavior; Behavioral; Blood Vessels; Brain; Brain-Derived Neurotrophic Factor; Bromodeoxyuridine; CD31 Antigens; Cells; Clinical; Clinical Research; Corpus striatum structure; Data; Development; Diffusion; Disease; Dopamine; Dopamine Receptor; Etiology; Event; Exercise; Extracellular Fluid; Family; Fluorescein-5-isothiocyanate; Functional disorder; Future; GDNF gene; Genes; Hippocampus (Brain); Immunohistochemistry; In Situ Hybridization; Individual; Intervention; Knock-out; Left; Legal patent; Measures; Microdialysis; Mitochondria; Modeling; Monitor; Motor; Motor Cortex; Nature; Neurons; Neurotoxins; PECAM1 gene; Parkinson Disease; Pharmacological Treatment; Prevention; Process; Proteins; Research; Respiration; Right-On; Role; Signal Transduction; Solid; Substantia nigra structure; Symptoms; Synapses; Testing; Therapeutic Intervention; Three-dimensional analysis; Tissues; Toxin; Vascular Endothelial Growth Factors; Western Blotting; angiogenesis; attenuation; base; density; design; disorder prevention; dopaminergic neuron; drug development; effective intervention; effective therapy; improved; insight; member; motor deficit; mouse model; multi-component intervention; neuron loss; neuroprotection; neurotrophic factor; novel; postsynaptic; preconditioning; programs; protective effect; receptor; receptor expression; response; tomato lectin; uptake

DESCRIPTION (provided by applicant): Parkinson's disease (PD) affects at least 1 million individuals in the US alone. Although much is known about its pathophysiology and information is emerging about its cause, there are no pharmacological treatments shown to have a significant, sustained impact on the prevention of PD or on attenuation of its progress. However, clinical evidence suggests that physical exercise is such a treatment, and this is supported by studies of animal models of the dopamine (DA) deficiency associated with the motor symptoms of PD. Moreover, exercise is a practical and sustainable therapeutic intervention likely to act simultaneously on most if not all of the cellular events capable of protecting DA neurons and restoring DA function. This proposal is designed test the hypothesis that exercise increases DA function and protects DA neurons against toxic insult due in part to increased neurotrophic factor (NTF) signaling, protection of mitochondrial respiration, and stimulation of angiogenesis. An MPTP mouse model will be used to test this hypothesis. Aim 1. To determine the effects of exercise on the impact of MPTP on dopaminergic function (1a) the optimal temporal relationship between exercise and toxin exposure will first be established, thus exploring both protection (exercise before toxin) and rescue (exercise after toxin). (1b) The impact of the optimal exercise paradigm on DA cell loss and on changes in pre- and post-synaptic DA receptors will then be assessed. (1c) Levels of DA and metabolites in striatal tissue and extracellular fluid will be measured in MPTP animals treated with exercise as dictated by Aim 1a. (1d) Mitochondrial respiration will be assessed after MPTP exercise. Aim 2. To assess the role of NTFs in exercise-induced protection members of four distinct NTF families known to protect DA neurons will be examined: GDNF, BDNF, MANF, and VEGF. (2a) The temporal and anatomical profile of NTF changes will be determined after exercise, MPTP, and the optimal combination of MPTP and exercise. (b) The ability of exogenous NTF to mimic the effects of exercise identified in Aim 1 will then be assessed. (2c) The NTFs and/or their receptors suggested by Aim 2a and 2b will be conditionally knocked out to determine if this increases the toxin impact of MPTP and reduces the protective impact of exercise, thereby strengthening the hypothesis of a causal relationship between NTF and exercise-induced protection. Aim 3. To examine the role of angiogenesis in exercise- and NTF-induced neuroprotection, (a) vasculature be assessed in substantia nigra, striatum, and cortex using BrdU to measure new cells and PECAM-1 (CD31), to mark blood vessels. (3b) FITC-conjugated tomato lectin will be used to detect patent blood vessels. (3c) A 3-dimensional analysis of vascular density will be performed. (3d) Finally, expression of angiogenesis-promoting proteins, including angiopoetins 1 and 2, will be measured. These results will provide the basis for the next iteration of a research program focusing on additional mechanisms underlying exercise-induced protection, provide stronger evidence for exercise-induced protection in PD, and establish targets for pharmacological treatment of the condition.

描述（由申请人提供）：仅在美国，帕金森病 (PD) 就影响至少 100 万人。尽管人们对其病理生理学了解甚多，并且有关其病因的信息不断涌现，但尚无任何药物治疗方法显示出对预防 PD 或减缓其进展具有显着、持续的影响。然而，临床证据表明，体育锻炼就是这样一种治疗方法，这一点得到了与 PD 运动症状相关的多巴胺 (DA) 缺乏的动物模型研究的支持。此外，运动是一种实用且可持续的治疗干预措施，可能同时作用于大多数（如果不是全部）能够保护 DA 神经元和恢复 DA 功能的细胞事件。该提案旨在测试以下假设：运动可增强 DA 功能并保护 DA 神经元免受毒性损伤，部分原因是神经营养因子 (NTF) 信号传导增加、线粒体呼吸保护和血管生成刺激。 MPTP 小鼠模型将用于检验这一假设。目的 1. 确定运动对 MPTP 对多巴胺能功能的影响 (1a) 首先建立运动与毒素暴露之间的最佳时间关系，从而探索保护（毒素前运动）和救援（毒素后运动） 。 (1b) 然后将评估最佳运动模式对 DA 细胞损失以及突触前和突触后 DA 受体变化的影响。 (1c) 将按照目标 1a 的规定，在接受运动治疗的 MPTP 动物中测量纹状体组织和细胞外液中的 DA 和代谢物水平。 (1d) MPTP 运动后将评估线粒体呼吸。目标 2. 为了评估 NTF 在运动诱导的保护中的作用，将检查已知保护 DA 神经元的四个不同 NTF 家族的成员：GDNF、BDNF、MANF 和 VEGF。 (2a) NTF 变化的时间和解剖学特征将在运动、MPTP 以及 MPTP 和运动的最佳组合后确定。 (b) 然后将评估外源性 NTF 模拟目标 1 中确定的运动效果的能力。 (2c) 目标 2a 和 2b 提出的 NTF 和/或其受体将被有条件地敲除，以确定这是否会增加 MPTP 的毒素影响并降低运动的保护作用，从而加强 NTF 和运动引起的保护。目标 3. 检查血管生成在运动和 NTF 诱导的神经保护中的作用，(a) 使用 BrdU 测量新细胞和 PECAM-1 (CD31) 来评估黑质、纹状体和皮质中的脉管系统以标记血管。 (3b) FITC 结合的番茄凝集素将用于检测开放血管。 (3c) 将进行血管密度的 3 维分析。 (3d)最后，将测量血管生成促进蛋白（包括血管生成素1和2）的表达。这些结果将为下一次研究项目提供基础，重点关注运动诱导保护的其他机制，为帕金森病的运动诱导保护提供更有力的证据，并建立该疾病的药物治疗目标。

项目成果

Parkinson's disease: Exit toxins, enter genetics.

帕金森病：排除毒素，进入遗传。

• 发表时间: 2010-02-09
• 影响因子: 6.7
• 作者: Westerlund, Marie;Hoffer, Barry;Olson, Lars
• 通讯作者: Olson, Lars

GDNF is not required for catecholaminergic neuron survival in vivo.

GDNF 不是儿茶酚胺能神经元在体内存活所必需的。

• 发表时间: 2015-03
• 影响因子: 25
• 作者: Kopra, Jaakko;Vilenius, Carolina;Grealish, Shane;Härma, Mari;Varendi, Kärt;Lindholm, Jesse;Castrén, Eero;Võikar, Vootele;Björklund, Anders;Piepponen, T Petteri;Saarma, Mart;Andressoo, Jaan
• 通讯作者: Andressoo, Jaan

HIF1α is necessary for exercise-induced neuroprotection while HIF2α is needed for dopaminergic neuron survival in the substantia nigra pars compacta.

HIF1α 是运动引起的神经保护所必需的，而 HIF2α 是黑质致密部多巴胺能神经元存活所必需的。

• 发表时间: 2015-06-04
• 影响因子: 3.3
• 作者: Smeyne, M;Sladen, P;Jiao, Y;Dragatsis, I;Smeyne, R J
• 通讯作者: Smeyne, R J

Commentary on chronic infusion of CDNF prevents 6-OHDA-induced deficits in a rat model of Parkinson's disease. Merja H. Voutilainen et al.

慢性输注 CDNF 可预防帕金森病大鼠模型中 6-OHDA 诱导的缺陷的评论。

• 发表时间: 2011-08
• 影响因子: 5.3
• 作者: Hoffer; Barry J
• 通讯作者: Barry J

CDNF protects the nigrostriatal dopamine system and promotes recovery after MPTP treatment in mice.

CDNF 保护黑质纹状体多巴胺系统并促进 MPTP 治疗小鼠后的恢复。

• 发表时间: 2012
• 影响因子: 3.3
• 作者: Airavaara, Mikko;Harvey, Brandon K;Voutilainen, Merja H;Shen, Hui;Chou, Jenny;Lindholm, Päivi;Lindahl, Maria;Tuominen, Raimo K;Saarma, Mart;Hoffer, Barry;Wang, Yun
• 通讯作者: Wang, Yun