Chaperones in Diabetic Peripheral Neuropathy

糖尿病周围神经病变的伴侣

• 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
• 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' 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

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。在寻求有效管理DPN的过程中，小分子抑制剂靶向了被认为是“糖尿病特异性”的蛋白质和途径以及在许多疾病状态下活性改变的其他蛋白质和途径。这些努力尚未产生任何显著的疗法，部分原因是这些靶点/途径对DPN进展的生化贡献在个体之间不具有时间和/或生化一致性的复杂问题。因此，我们寻求合理识别一种新的分子范式，该范式提供了“可药物化”的靶点，并为疾病进展的各个阶段的DPN的有效医疗管理提供了转化潜力。在复杂的慢性神经退行性疾病如阿尔茨海默病和DPN中，人们越来越认识到，有效的疾病管理可能不一定需要靶向被认为有助于疾病进展的途径或蛋白质。或者，它可能被证明是有益的，从而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，我们合成了一种新的小分子，通过抑制分子伴侣热休克蛋白90（Hsp 90）激活内源性细胞保护反应。热休克蛋白90是细胞保护性热休克反应的主要调节因子，其上调热休克蛋白70和抗氧化基因的表达。我们的先导化合物是一种称为KU-32的无毒，生物可利用的分子，我们提供的证据表明，它逆转了DPN的多个临床指标，促进受损感觉纤维恢复和神经再支配到表皮中，增加线粒体生物能量学并降低1型和2型糖尿病模型中的氧化应激。从机制上讲，用KU-32抑制Hsp 90诱导糖尿病背根神经节中的其他分子伴侣，如细胞溶质Hsp 70和线粒体Hsp 70（mtHsp 70）。重要的是，KU-32的功效需要Hsp 70，因为该药物在逆转糖尿病Hsp 70 KO小鼠中的DPN方面无效。为了响应从动物和原代细胞模型收集的一组全面的初步数据，我们广泛的假设是，调节Hsp 70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来拯救感觉神经元免受高血糖应激。为了解决这一假设，目的一将确定通过KU-32逆转DPN的临床指标是否需要感觉神经元的线粒体生物能量学的Hsp 70依赖性增加。目的2将确定热休克蛋白70是否通过降低成年感觉神经元的氧化应激来增强线粒体生物能量学。目的3将确定Hsp 70和mtHsp 70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。我们工作的结果将为Hsp 70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学管理DPN的可行方法。