Mitochondrial protection of a GDNF propeptide

GDNF 前肽的线粒体保护

基本信息

批准号：
8166442
负责人：
Luke H Bradley
金额：
$ 7.43万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8166442
关键词：
Affect Agriculture American Amino Acids Attention Bioenergetics Biological Response Modifier Therapy Bradykinesia Brain Cell Culture Techniques Cell Death Cell Line Cells Chronic Complex Data Development Disadvantaged Dopaminergic Cell Endopeptidases Etiology Evaluation Event Exhibits Exposure to Family Future Goals Growth Factor Hand Individual Measures Mitochondria Modeling Names Nervous system structure Neurobiology Neurotoxins Occupational Parkinson Disease Parkinsonian Disorders Pathogenesis Patients Peptides Pilot Projects Posture Predisposition Property Proteins Proteomics Rattus Research Respiration Respiratory Chain Rest Site Stress Symptoms Testing Therapeutic Therapeutic Agents Toxic Environmental Substances Toxin Tremor aged base clinical application dopaminergic neuron equilibration disorder glial cell-line derived neurotrophic factor mitochondrial dysfunction nervous system disorder neurotrophic factor novel protective effect respiratory response restoration

项目摘要

DESCRIPTION (provided by applicant): Mitochondrial dysfunction has been identified as one of the key players in Parkinson's disease (PD) pathogenesis. While the etiology is unknown in most cases, the development of progressive parkinsonian symptoms has been shown in patients following exposure to various environmental and occupational toxins. Numerous studies demonstrate that these neurotoxins specifically inhibit the mitochondrial respiratory chain complexes of dopaminergic neurons, which initiates a cascade of events ultimately leading to cell death. Furthermore, the susceptibility to environmental neurotoxins is increased in the aged nervous system. Thus for the long-term treatment of PD and parkinsonian symptoms, therapeutic strategies are needed that not only restore dopaminergic neuron function, but also provide mitochondrial protection and restoration from various stresses, including environmental toxin exposure. In the past, neurotrophic growth factors have received considerable attention as potential therapeutic agents for neurological disorders. However, the clinical application of these native molecules has not advanced primarily due to pharmacological disadvantages and challenges associated with directly delivering large protein molecules to the brain. The emergence of physiologically functional propeptides from the neurotrophic factor family provides a wealth of novel, smaller sequences for biotherapeutic exploration and evaluation. Examination of the glial cell line-derived neurotrophic factor (GDNF) prosequence predicts internal dibasic endopeptidase sites that would yield a smaller, amidated eleven amino acid residue peptide named dopamine neuron stimulating peptide-11 (DNSP-11). Recent evaluation of DNSP-11 has shown that it exhibits similar GDNF-like neurotrophic responses in normal and parkinsonian rat models. However, cell culture and proteomic pull-down data suggest that DNSP-11 functions differently than mature GDNF; leading to our hypothesis that DNSP-11's neurobiological actions are through the mitochondria. The research outlined in the current proposal will measure DNSP-11's bioenergetic and protective effects, in the MN9D dopaminergic cell line, from toxins that specifically target the mitochondrial respiratory complexes. The information obtained in this study will further our understanding of this propeptide's neurobiological activity and provide the basis for future evaluation and biotherapeutic development of DNSP-11. PUBLIC HEALTH RELEVANCE: Parkinson's disease (PD), a chronic neurological disorder that affects over 1 million Americans, is characterized by stooped posture, balance impairments, rigidity, resting hand tremors, and bradykinesia. While the cause of PD is largely unknown, parkinsonian symptoms have been shown to develop following long-term exposure to common environmental toxins that specifically target the mitochondria of dopamine neurons. The goal of this pilot project is to investigate the neuroprotective properties of a novel neurotrophic propeptide, DNSP-11, from mitochondrial-specific toxins to pave the way for its downstream evaluation as a potential PD therapeutic.

描述（由申请人提供）：线粒体功能障碍已被确定为帕金森病（PD）发病机制的关键因素之一。虽然大多数病例的病因尚不清楚，但在接触各种环境和职业毒素后，患者会出现进行性帕金森病症状。大量研究表明，这些神经毒素特异性抑制多巴胺能神经元的线粒体呼吸链复合物，从而引发一系列级联事件，最终导致细胞死亡。此外，老年神经系统对环境神经毒素的敏感性增加。因此，对于帕金森病和帕金森病症状的长期治疗，需要的治疗策略不仅要恢复多巴胺能神经元功能，还要提供线粒体保护和恢复免受各种压力（包括环境毒素暴露）的影响。过去，神经营养生长因子作为神经系统疾病的潜在治疗剂受到了相当多的关注。然而，这些天然分子的临床应用尚未取得进展，主要是由于与直接将大蛋白质分子递送至大脑相关的药理学缺点和挑战。神经营养因子家族中生理功能前肽的出现为生物治疗探索和评估提供了丰富的新颖、较小的序列。对神经胶质细胞系衍生的神经营养因子 (GDNF) 原序列的检查预测内部二碱基内肽酶位点，该位点将产生较小的酰胺化 11 个氨基酸残基肽，称为多巴胺神经元刺激肽-11 (DNSP-11)。最近对 DNSP-11 的评估表明，它在正常和帕金森病大鼠模型中表现出类似 GDNF 样神经营养反应。然而，细胞培养和蛋白质组下拉数据表明 DNSP-11 的功能与成熟的 GDNF 不同；导致我们假设 DNSP-11 的神经生物学作用是通过线粒体进行的。当前提案中概述的研究将测量 DNSP-11 在 MN9D 多巴胺能细胞系中，来自专门针对线粒体呼吸复合物的毒素的生物能和保护作用。本研究获得的信息将进一步我们对该前肽的神经生物学活性的理解，并为 DNSP-11 的未来评估和生物治疗开发提供基础。公共卫生相关性：帕金森病 (PD) 是一种影响超过 100 万美国人的慢性神经系统疾病，其特点是弯腰、平衡障碍、僵硬、静止性手震颤和运动迟缓。虽然帕金森病的病因在很大程度上尚不清楚，但帕金森病症状已被证明是在长期暴露于专门针对多巴胺神经元线粒体的常见环境毒素后出现的。该试点项目的目标是研究线粒体特异性毒素中新型神经营养性前肽 DNSP-11 的神经保护特性，为其作为潜在 PD 治疗剂的下游评估铺平道路。