Bladder Dysfunction and Dysregulation of Neurotransmission

膀胱功能障碍和神经传递失调

• 批准号: 10485445
• 负责人: MARYROSE P SULLIVAN
• 金额: --
• 依托单位: VA BOSTON HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2026-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10485445
• 关键词: Acceleration; Actins; Address; Age; Aging; Agonist; Amyloid; Animal Disease Models; Animal Model; Antidiabetic Drugs; Biochemical; Biological Process; Bladder; Bladder Diseases; Bladder Dysfunction; Brain; Cerebrospinal Fluid; Chronic Disease; Cohort Studies; Complex; Complications of Diabetes Mellitus; Cytoskeleton; Data; Defect; Deposition; Diabetes Mellitus; Disease; Disease Progression; Distress; Docking; Early Intervention; Early identification; Emotional; Epidemiology; Event; Exocytosis; Family; Foundations; Functional disorder; GLP-I receptor; General Population; Health; Hyperglycemia; Impaired cognition; Impairment; In Vitro; Lower urinary tract; Mediating; Methods; Molecular; Molecular Conformation; Motor; Myosin ATPase; Nerve; Nerve Degeneration; Nerve Fibers; Neurodegenerative Disorders; Neurogenic Bladder; Non-Insulin-Dependent Diabetes Mellitus; Parkinson Disease; Pathogenesis; Pathologic; Pathology; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phosphorylation; Physiological; Prevalence; Primates; Process; Property; Proteins; Psyche structure; Quality of life; Risk; Role; Series; Severities; Signal Transduction; Symptoms; Synaptic Vesicles; Techniques; Testing; Therapeutic; Varicosity; Veterans; adverse outcome; alpha synuclein; blood glucose regulation; comorbidity; design; diabetic; effective intervention; functional restoration; genome wide association study; glucagon-like peptide; glucagon-like peptide 1; glucose metabolism; glycation; health care delivery; high risk; improved; insight; loss of function; military veteran; mortality risk; motor function improvement; motor impairment; multidisciplinary; nerve supply; neuropathology; neuroprotection; neurotoxicity; neurotransmission; novel; presynaptic; presynaptic neurons; psychologic; response; restoration; social; trafficking; treatment strategy

Bladder dysfunction is a common, distressing finding in patients afflicted with two disorders that are increasingly prevalent in the general population but significantly over- represented in the veteran population—type 2 diabetes (T2DM) and Parkinson’s disease (PD). Currently, treatments for bladder dysfunction address the symptoms, not the cause, which remains largely unknown. Though bladder dysfunction manifests early in the course of each disease, it frequently remains unrecognized and worsens with disease progression. T2DM and PD can occur independently, however these disorders are related and sometimes coincident. It has been shown that T2DM increases the risk of PD, and PD patients with T2DM develop more aggressive motor and cognitive impairment. Such reciprocity is likely to spring from a common biochemical mechanism underlying the pathogenesis of both chronic diseases, with adverse consequences for bladder function. The pathology of PD is associated with aggregation of alpha synuclein (αSyn), a protein abundant in presynaptic nerve varicosities whose biological function, though incompletely understood, encompasses a role in facilitation of neurotransmission. In this proposal, we present and rigorously test our proposed mechanism of αSyn interaction with the unconventional motor protein, myosin 5a (Myo5a), as well as with cytoskeletal actin, in functional processes involving neurotransmission and glucose regulation in the bladder. We will examine perturbation of this mechanism in both T2DM and PD animal models and under in vitro hyperglycemic conditions. We also propose to investigate the influence of glucagon-like peptide agonists, agents used in T2DM treatment, on restoring the αSyn-Myo5a-actin axis. The multidisciplinary studies proposed herein will integrate biochemical, molecular, cellular and physiological approaches that exploit state of the art methods combined with proven conventional techniques. The information gained will provide a foundation for more effective interventions addressing the foundational causes of bladder dysfunction and deficits in bladder neurotransmission in patients with T2DM and PD.

膀胱功能障碍是一种常见的，令人痛苦的发现，患者患有两个 这些疾病在普通人群中越来越普遍，但明显超过- 以退伍军人为代表的2型糖尿病（T2 DM）和帕金森病（PD）。 目前，膀胱功能障碍的治疗解决了症状，而不是原因， 仍然是未知的。虽然膀胱功能障碍在每个过程中的早期表现， 疾病，它往往仍然未被认识和疾病进展的困扰。t2 dm和 PD可以独立发生，但这些疾病是相关的，有时是同时发生的。它 研究表明，T2 DM增加了PD的风险，并且患有T2 DM的PD患者更容易发生PD。 攻击性运动和认知障碍。这种互惠可能源于一种共同的 这两种慢性疾病的发病机制的生化机制，与不利的 膀胱功能的后果。PD的病理学与α-淀粉样蛋白的聚集有关， 突触核蛋白（αSyn）是一种在突触前神经曲张中含量丰富的蛋白质， 尽管尚未完全理解，但其包括促进神经传递的作用。在这 建议，我们提出并严格测试我们提出的αSyn相互作用的机制， 肌球蛋白5a（Myo 5a），以及与细胞骨架肌动蛋白，在功能上， 膀胱中涉及神经传递和葡萄糖调节的过程。我们将研究 在T2 DM和PD动物模型中以及在体外条件下， 高血糖状况。我们还建议研究胰高血糖素样肽的影响 激动剂，T2 DM治疗中使用的药物，恢复α Syn-Myo 5a-肌动蛋白轴。的 本文提出的多学科研究将整合生物化学、分子、细胞和 利用现有技术的方法与已证实的常规方法相结合的生理方法 技术.所获得的信息将为更有效的干预措施奠定基础 解决膀胱功能障碍和膀胱缺陷的根本原因 T2 DM和PD患者的神经传递。