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Dysregulation of Neurotransmission in the Bladder with Parkinson's Disease

帕金森病膀胱神经传递失调

基本信息

批准号：
9239723
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
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9239723
关键词：
Address Age Aging Animal Model Animals Appearance Area Automobile Driving Basal Ganglia Biological Assay Bladder Bladder Control Bladder Diseases Bladder Dysfunction Bladder Tissue Bradykinesia Brain Brain region Case Study Cell Nucleus Clinical Colon Complex Consequentialism Constipation Data Defect Development Diagnosis Disease Disinhibition Docking Early Intervention Emotional Epidemiology Etiology Event Exocytosis Foundations Functional disorder Health Health Care Costs Human Impairment In Vitro Incontinence Inferior hypogastric plexus structure Institutionalization Investigation Lead Lesion Levodopa Lewy Bodies MYO5A gene Mediating Membrane Micturition Reflex Molecular Motor Movement Disorders Mus Mutation Myosin ATPase Nerve Nerve Degeneration Nerve Fibers Neuraxis Neurites Neurogenic Bladder Neurologic Nocturia Organ Overactive Bladder Parkinson Disease Pathogenesis Pathologic Pathology Pathway interactions Patients Peripheral Peripheral Nerves Pharmacotherapy Phase Phenotype Physiological Population Process Proteins Psyche structure Quality of life Reflex action Regulation Reporting Rest Tremor Risk Role Secretory Vesicles Services Structure Substantia nigra structure Symptoms Synapses Synaptic Vesicles Time Transgenic Animals Transgenic Mice Transport Vesicles Urination Varicosity Ventricular Cardiac alpha-Myosin Vesicle Veterans Visceral age related alpha synuclein alpha synuclein gene cholinergic design dopaminergic neuron early onset falls health care delivery in vivo insight lower urinary tract symptoms motor deficit motor symptom mouse model mutant neurochemistry neuropathology neuroregulation neurotransmission neurotransmitter release non-motor symptom novel pars compacta posture instability prevent protein protein interaction response social trafficking treatment strategy urinary

项目摘要

Bladder dysfunction is highly prevalent and often debilitating in patients with Parkinson’s disease (PD), a progressive movement disorder characterized by the appearance of abnormal aggregated α-synuclein in various brain regions. Lower urinary tract symptoms (incontinence, urgency, nocturia, etc.) in patients with PD are generally attributed to neurologic defects in the central inhibition of micturition centers in the brain that result in detrusor overactivity. However, a direct effect of α-synuclein pathology on peripheral neural control of bladder function has not been previously examined. Moreover, recent epidemiological evidence suggests that non-motor symptoms may substantially precede the development of movement disorders in patients with PD. These factors have prompted us to re-examine the pathophysiology of neurogenic bladder dysfunction in PD and address the novel hypothesis that peripheral regulation of local neurotransmission in the bladder is significantly altered in early stage PD, prior to the onset of motor deficits. Our first aim will be to demonstrate that pathologic α-synuclein expression in PD causes temporal changes in bladder neurotransmission and contractile function that precede somatomotor deficits. We will exploit transgenic animal models of PD that express either the wild-type human α- synuclein gene or a mutant human α-synuclein gene found in a form of familial PD. The bladder phenotype of these animals will be comprehensively characterized at increasing ages using in vitro and in vivo functional assays. These studies will allow us to assess the physiologic role of local α-synuclein and determine the impact of pathologic α-synuclein on bladder function. Our preliminary data indicate that α-synuclein is highly expressed in human and mouse nerve fibers within the bladder and that the functional response to nerve stimulation is dramatically altered in bladders from mice with α-synuclein mutation. These findings suggest an important role for α-synuclein in synaptic vesicle transport, in a pathway that is shared by myosin Va, a processive motor protein that we have previously shown to be involved in vesicular trafficking and neurotransmission in visceral organs. Our preliminary data suggests a relevant intramolecular relationship between myosin Va and α-synuclein. Therefore, in specific aim 2, we will determine the extent to which α-synuclein-myosin Va protein interactions influence neurotransmission in the bladder. The interaction between myosin Va and α-synuclein will be assessed in bladder tissue under physiologic conditions using molecular and cellular approaches. This physiologic protein- protein interaction will be compared with the defective interaction in the bladder that occurs with PD and correlated with changes in the level of neurotransmitters released from isolated bladder nerves. At the conclusion of these studies, we will have: (1) provided new insights regarding the physiologic function of α- synuclein in peripheral nerves; (2) determined whether local defects in neurotransmission contribute to bladder dysfunction in early stages of PD; (3) established the time course of these changes; (4) confirmed a role for α- synuclein - myosin Va interactions in regulating synaptic vesicle trafficking; and (5) assessed how aberrant interactions impact neurotransmitter release. The next phase of the project will include a more detailed investigation of dysfunctional neurotransmission in the bladder during early PD and of α- synuclein -myosin Va interactions that underlie those deficits. Findings from this project will ultimately advance our current understanding of the pathophysiology of neurogenic bladder dysfunction in PD and may provide the foundation for the design of better targeted pharmacotherapy for the neurogenic bladder.