Chaperones in Diabetic Peripheral Neuropathy

糖尿病周围神经病变的伴侣

基本信息

批准号：
8628112
负责人：
Rick T Dobrowsky
金额：
$ 32.59万
依托单位：
UNIVERSITY OF KANSAS LAWRENCE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-03-01 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8628112
关键词：
Address Adult Afferent Neurons Alzheimer&apos s Disease American Amino Acids Animals Antioxidants Binding Bioavailable Biochemical Bioenergetics Blood Glucose Blood Vessels Cell model Cellular Stress Chaperone Gene Chronic Clinical Complement Complex Data Diabetes Mellitus Diabetic Neuropathies Disease Disease Management Disease Progression Epidermis Etiology Family member Fiber Genes Glucose HSP 90 inhibition Heat-Shock Proteins 70 Heat-Shock Proteins 90 Heat-Shock Response Hyperglycemia Individual Insulin Kinetics Knock-out Knockout Mice Knowledge Lead Link Manganese Superoxide Dismutase Medical Metabolic Metabolic Control Mitochondria Mitochondrial Proteins Modeling Modification Molecular Molecular Chaperones Nerve Degeneration Neurodegenerative Disorders Neurons Neuropathy Non-Insulin-Dependent Diabetes Mellitus Oral Outcome Oxidative Stress Pathway interactions Patients Peripheral Nervous System Diseases Pharmaceutical Preparations Protein Import Proteins Psychophysics Publishing Recovery Respiration Role Sensory Series Spinal Ganglia Staging Stress Structure Symptoms Testing Therapeutic Up-Regulation Wild Type Mouse Work diabetes management diabetic drug efficacy improved indexing inhibitor/antagonist innovation insight mitochondrial dysfunction novel paralogous gene polypeptide protein aggregate protein folding public health relevance reinnervation respiratory response small molecule stress tolerance success type I and type II diabetes

项目摘要

DESCRIPTION (provided by applicant): The etiology of diabetic peripheral neuropathy (DPN) involves an inter-related series of metabolic and vascular insults that ultimately contribute to sensory neuron degeneration. In the quest to pharmacologically manage DPN, small molecule inhibitors have targeted proteins and pathways regarded as "diabetes specific" as well as others whose activity are altered in numerous disease states. These efforts have not yielded any significant therapies, due in part to the complicating issue that the biochemical contribution of these targets/pathways to the progression of DPN does not occur with temporal and/or biochemical uniformity between individuals. Thus, we have pursued the rational identification of a new molecular paradigm that offers a "druggable" target and provides translational potential for effective medical management of DPN at various stages of disease progression. In complex, chronic neurodegenerative diseases such as Alzheimer's disease and DPN, it is increasingly appreciated that effective disease management may not necessarily require targeting a pathway or protein considered to contribute to disease progression. Alternatively, it may prove beneficial to pharmacologically enhance the activity of endogenous neuroprotective pathways to aid neuronal recovery and stress tolerance. To this end, we have synthesized a novel small molecule that activates an endogenous cytoprotective response by inhibiting the molecular chaperone, heat shock protein 90 (Hsp90). Hsp90 is the master regulator of the cytoprotective heat shock response, which upregulates expression of Hsp70 and antioxidant genes. Our lead compound is a non-toxic, bioavailable molecule called KU-32 and we provide evidence that it reverses multiple clinical indices of DPN, promotes the recovery and reinnervation of damaged sensory fibers into the epidermis, increases mitochondrial bioenergetics and decreases oxidative stress in models of Type 1 and Type 2 diabetes. Mechanistically, inhibiting Hsp90 with KU-32 induces other chaperones such as cytosolic Hsp70 and mitochondrial Hsp70 (mtHsp70) in diabetic dorsal root ganglia. Importantly, the efficacy of KU-32 requires Hsp70 since the drug is ineffective in reversing DPN in diabetic Hsp70 KO mice. In response to a comprehensive set of preliminary data gathered from animal and primary cell models, our broad hypothesis is that modulating Hsp70 and its paralogs can rescue sensory neurons from hyperglycemic stress by antagonizing aspects of glucose-induced mitochondrial dysfunction. To address this hypothesis, aim one will identify if reversing the clinical indices of DPN by KU-32 requires an Hsp70-dependent increase in mitochondrial bioenergetics of sensory neurons. Aim 2 will determine if Hsp70 enhances mitochondrial bioenergetics by decreasing oxidative stress in adult sensory neurons. Aim 3 will identify if Hsp70 and mtHsp70 augment mitochondrial function by increasing protein import in diabetic neurons. The outcomes of our work will provide fundamental molecular insight into how Hsp70 paralogs improve sensory neuron bio- energetics and validate that modulating molecular chaperones is a viable approach to medically manage DPN.

描述（由申请人提供）：糖尿病周围神经病变（DPN）的病因涉及一系列相互关联的代谢和血管损伤，最终导致感觉神经元变性。在寻求药物管理 DPN 的过程中，小分子抑制剂靶向被视为“糖尿病特异性”的蛋白质和途径，以及在多种疾病状态下其活性发生改变的其他蛋白质和途径。这些努力尚未产生任何重要的治疗方法，部分原因是这些靶点/途径对 DPN 进展的生化贡献并不随着个体之间的时间和/或生化一致性而发生。因此，我们寻求合理鉴定一种新的分子范式，该范式提供“可成药”靶标，并为 DPN 在疾病进展的各个阶段的有效医疗管理提供转化潜力。在复杂的慢性神经退行性疾病（例如阿尔茨海默病和 DPN）中，人们越来越认识到有效的疾病管理可能不一定需要针对被认为有助于疾病进展的途径或蛋白质。或者，它可能被证明有益于在药理学上增强内源性神经保护途径的活性，以帮助神经元恢复和应激耐受。为此，我们合成了一种新型小分子，它通过抑制分子伴侣热休克蛋白 90 (Hsp90) 来激活内源性细胞保护反应。 Hsp90 是细胞保护性热休克反应的主要调节因子，可上调 Hsp70 和抗氧化基因的表达。我们的先导化合物是一种无毒、生物可利用的分子，称为 KU-32，我们提供的证据表明它可以逆转 DPN 的多种临床指标，促进受损感觉纤维的恢复和神经支配进入表皮，增加线粒体生物能并减少模型中的氧化应激1 型和 2 型糖尿病。从机制上讲，用 KU-32 抑制 Hsp90 会诱导糖尿病背根神经节中的其他伴侣，例如胞质 Hsp70 和线粒体 Hsp70 (mtHsp70)。重要的是，KU-32 的功效需要 Hsp70，因为该药物无法有效逆转糖尿病 Hsp70 KO 小鼠的 DPN。根据从动物和原代细胞模型收集的一套全面的初步数据，我们的广泛假设是，调节 Hsp70 及其旁系同源物可以通过拮抗葡萄糖诱导的线粒体功能障碍，将感觉神经元从高血糖应激中拯救出来。为了解决这一假设，目标之一是确定通过 KU-32 逆转 DPN 的临床指标是否需要 Hsp70 依赖性增加感觉神经元的线粒体生物能。目标 2 将确定 Hsp70 是否通过减少成人感觉神经元的氧化应激来增强线粒体生物能。目标 3 将确定 Hsp70 和 mtHsp70 是否通过增加糖尿病神经元中的蛋白质输入来增强线粒体功能。我们的工作成果将为 Hsp70 旁系同源物如何改善感觉神经元生物能量学提供基本的分子见解，并验证调节分子伴侣是医疗管理 DPN 的可行方法。