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（DPN）的病因涉及一系列相关的代谢和血管损伤，最终导致感觉神经元变性。为了通过药理管理DPN，小分子抑制剂的靶向蛋白质和途径被视为“特定糖尿病”，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重要的疗法，部分原因是，这些靶标/途径对DPN进展的生化贡献并不是个人之间的时间和/或生化均匀性的生化贡献。因此，我们追求了一种新的分子范式的合理识别，该范式提供了“可药”目标，并为在疾病进展的各个阶段有效地对DPN的医学管理提供了转化潜力。在复杂的，慢性神经退行性疾病（例如阿尔茨海默氏病）和DPN，越来越多地认为，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。另外，它可能证明有益于药理学增强内源性神经保护途径的活性，以帮助神经元恢复和胁迫耐受性。为此，我们合成了一个新型的小分子，该分子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是细胞保护热反应的主要调节剂，它上调了HSP70和抗氧化基因的表达。我们的铅化合物是一种称为KU-32的无毒的生物利用分子，我们提供的证据表明，它逆转了DPN的多个临床指数，促进了受损的感觉纤维的恢复和加重，将受损的感觉纤维恢复到表皮中，从而增加了线粒体生物烯烃，并减少1型和类型2型号的氧化应激。从机械上讲，用KU-32抑制HSP90会诱导其他伴侣，例如胞质HSP70和线粒体HSP70（MTHSP70）在糖尿病背部根神经节中。重要的是，KU-32的疗效需要HSP70，因为该药物在逆转DPN中逆转糖尿病HSP70 KO小鼠。为了响应从动物和主要细胞模型中收集的一组全面的初步数据，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的方面来从高血糖应激中拯救感觉神经元。为了解决这一假设，AIM将确定KU-32逆转DPN的临床指数是否需要HSP70依赖性依赖的感觉神经元的线粒体生物能学。 AIM 2将通过减少成人感觉神经元的氧化应激来确定HSP70是否可以增强线粒体生物能。 AIM 3将通过增加在糖尿病神经元中进口的蛋白质进口的HSP70和MTHSP70是否增强线粒体功能。我们工作的结果将为HSP70旁系同源物如何改善感觉神经元生物能力并验证调节分子伴侣是一种可行的医学管理DPN的方法。