TNF-alpha activation of Rho-kinase in cavernous nerve injury

海绵体神经损伤中 TNF-α 激活 Rho 激酶

• 批准号: 8680884
• 负责人: Trinity Jude Bivalacqua
• 金额: $ 8.1万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8680884
• 关键词: Address; Aftercare; Aging; Animal Model; Apoptosis; Award; Axon; Biological Preservation; Biology; Cells; Complication; Cytokine Network Pathway; Data; Development; Diabetes Mellitus; Diagnosis; Disease; Enzyme-Linked Immunosorbent Assay; Enzymes; Erectile dysfunction; Event; Functional disorder; Funding; Ganglia; Genomics; Grant; Growth; Immunofluorescence Immunologic; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injury; Intervention; Lead; Link; Macrophage Activation; Malignant neoplasm of prostate; Measurement; Mediator of activation protein; Medicine; Modeling; Modification; Molecular; Monocyte Chemoattractant Protein-1; National Institute of Diabetes and Digestive and Kidney Diseases; Natural regeneration; Nerve; Nerve Degeneration; Nerve Fibers; Nerve Regeneration; Nervous system structure; Neuraxis; Neurites; Neurons; Neuropathy; Nitric Oxide Synthase Type I; Organ; Outcome; Pathway interactions; Pelvis; Penile Erection; Peripheral; Peripheral Nerves; Peripheral Nervous System; Peripheral nerve injury; Phosphorylation; Physiology; Play; Postoperative Period; Process; Production; Proteins; Quality of life; Radiation therapy; Radical Prostatectomy; Rattus; Research; Rho-associated kinase; Role; Schwann Cells; Signal Pathway; Signal Transduction; Site; Stimulus; Structure; Surgical Management; Synaptic Transmission; TNF gene; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; United States; Up-Regulation; Wallerian Degeneration; Western Blotting; Work; axon growth; axon guidance; axon regeneration; axonal degeneration; base; cancer diagnosis; cancer therapy; caspase-3; chemokine; cytokine; erection; extracellular; feeding; genome wide association study; hemodynamics; hormone therapy; human TNF protein; improved; in vivo; inhibitor/antagonist; insight; macrophage; men; mesangial cell; monocyte; monocyte chemoattractant protein 1 receptor; nerve injury; nerve supply; neuroinflammation; neuron loss; neuronal cell body; neurophysiology; novel; novel therapeutics; penis; prevent; public health relevance; regenerative; research study; treatment strategy

DESCRIPTION (provided by applicant): Major sequela from the surgical management of prostate cancer is post-operative erectile dysfunction (ED). Advances in the field of neurourology have focused on the development and implementation of strategies for preserving the neurogenic basis of penile erection and functional integrity of the cavernous nerves (CN) following RP and thus maximizing postoperative erectile function outcomes. Following injury to the autonomic CN, there is a microenvironment change that predisposes the axons to degeneration with a proportion of nerve fibers which will regenerate with neurotrophic stimulus. The cellular and molecular mechanisms promoting neuropathy following CN injury is only recently been investigated with strong support for the involvement of cytokine induction and inflammatory mechanisms which lead to axonal degeneration. Now, the major challenge is identifying the key molecular events and signal transduction networks which lead to CN degeneration after injury or even in disease states such as diabetes mellitus and aging. This work is of particular importance because identification of key molecular switches that lead to CN dysfunction may lead to new treatment paradigms for this important problem in sexual medicine. In this application, we propose to address these issues by studying how the cytokine (TNF-?) and inflammatory (macrophage) milieu serve as a critical upstream activator of RhoA/Rho-kinase (ROCK) signaling in the major pelvic ganglion (MPG) after CN injury. Activation of ROCK signaling in the MPG promotes neuronal cell body apoptosis and thus reduction of synaptic transmission through the CN to the end-organ penis. Using a combination of in vitro myograph experiments, ex vivo explanted MPG measurements of neuritogenesis, and in vivo erectile physiology hemodynamic changes in an animal model of CN injury, we are poised to extend our work on RhoA/ROCK signaling in the MPG which was funded by a previous NIDDK K08 award application. As cytokines, macrophage chemoattraction, and ROCK signaling is easily manipulated by pharmacologic inhibitors, this work will not only add to our basic understanding of CN pathophysiology after injury, but also provide potential new therapeutic options for neurogenic-ED.

描述（申请人提供）：前列腺癌手术治疗的主要后遗症是术后勃起功能障碍（ED）。神经病学领域的进展主要集中在发展和实施策略，以保护阴茎勃起的神经源性基础和海绵状神经（CN）的功能完整性，从而最大限度地提高术后勃起功能。自主神经CN损伤后，微环境变化使轴突退化，部分神经纤维在神经营养刺激下再生。神经损伤后促进神经病变的细胞和分子机制直到最近才被研究，并有力地支持细胞因子诱导和炎症机制的参与，导致轴突变性。目前，主要的挑战是确定损伤后甚至糖尿病和衰老等疾病状态下导致CN变性的关键分子事件和信号转导网络。这项工作特别重要，因为鉴定导致CN功能障碍的关键分子开关可能会为性医学中的这一重要问题带来新的治疗范例。在本应用中，我们建议通过研究细胞因子（TNF-）和炎症（巨噬细胞）环境如何在CN损伤后主要盆腔神经节（MPG）中作为RhoA/ rho激酶（ROCK）信号传导的关键上游激活剂来解决这些问题。MPG中ROCK信号的激活促进神经元细胞体凋亡，从而减少通过CN到末端器官阴茎的突触传递。通过结合体外肌图实验、神经生成的体外外植体MPG测量以及CN损伤动物模型的体内勃起生理血流动力学变化，我们准备扩展我们在MPG中的RhoA/ROCK信号的工作，该工作由之前的NIDDK K08奖申请资助。由于细胞因子、巨噬细胞的化学吸引和ROCK信号很容易被药物抑制剂控制，这项工作不仅增加了我们对CN损伤后病理生理的基本认识，而且为神经源性ed的治疗提供了潜在的新选择。