Roles of RhoA/Rho-kinase Signaling in Cavernous Neurons Following Axonal Injury

RhoA/Rho 激酶信号传导在轴突损伤后海绵体神经元中的作用

• 批准号: 8306117
• 负责人: Trinity Jude Bivalacqua
• 金额: $ 15.87万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8306117
• 关键词: Address; Aftercare; American; Animal Model; Apoptosis; Area; Award; Axon; Basic Science; Bioinformatics; Biological Assay; Biological Preservation; Cardiovascular Diseases; Cells; Cellular Structures; Cellular biology; Chromosome Mapping; Clinical; Clinical Sciences; Complement; Complication; Crush Injury; Data; Development; Diabetes Mellitus; Diagnosis; Disease; Doctor of Philosophy; Dominant-Negative Mutation; Dorsal; Education; Electron Microscopy; Endothelial Cells; Enzymes; Equilibrium; Erectile dysfunction; Event; Family; Fellowship; Foundations; Functional disorder; Funding; Ganglia; Gene Delivery; Gene Expression Profiling; Genes; Genetic; Genitourinary system; Goals; Grant; Growth; Guanosine Triphosphate Phosphohydrolases; Health; Histology; Immunofluorescence Immunologic; In Vitro; Incontinence; Individual; Injury; Institutes; Intrinsic factor; Investigation; K-Series Research Career Programs; Lead; Link; Lower urinary tract; Malignant neoplasm of prostate; Mediating; Mentors; Mentorship; Modeling; Modification; Molecular; Morphology; Natural regeneration; Nerve; Nerve Crush; Nerve Regeneration; Nervous System Physiology; Nervous System Trauma; Nervous system structure; Neuraxis; Neurites; Neurobiology; Neurons; Neuropathy; Neurosciences; Outcome; Pathogenesis; Pathway interactions; Patient Care; Pelvis; Penile Erection; Peripheral; Peripheral Nerves; Peripheral Nervous System; Pharmacology; Pharmacotherapy; Physiological; Physiology; Postdoctoral Fellow; Postoperative Period; Prevention; Priapism; Process; Program Research Project Grants; Prostatectomy; Quality of life; Radiation therapy; Radical Prostatectomy; Rattus; Recording of previous events; Recovery; Research; Research Personnel; Residencies; Resources; Rho-associated kinase; Role; Schwann Cells; Scientist; Series; Sickle Cell Anemia; Signal Pathway; Signal Transduction; Simplexvirus; Stimulus; Stretching; Structure; Surgeon; Surgical Management; Synaptic Transmission; Systemic disease; Therapeutic; Time; Training; United States; United States National Institutes of Health; Universities; Urinary Incontinence; Urogenital Diseases; Urology; Western Blotting; axon growth; axon guidance; axon regeneration; axonal degeneration; base; cancer diagnosis; cancer therapy; career; career development; cell motility; clinical practice; design; experience; extracellular; genome wide association study; hormone therapy; improved; in vivo; inhibitor/antagonist; injured; insight; intervention effect; member; men; mutant; nerve injury; neurodevelopment; neuron apoptosis; neuron loss; neuronal growth; neuropathology; neurophysiology; neuroprotection; novel; programs; regenerative; repaired; research study; response; response to injury; rho; skills; success; urologic

DESCRIPTION (provided by applicant): My proposed Mentored Clinical Scientist Research Career Development (K08) Award will focus on a research topic which has tremendous potential to impact the field of Neurourology. Prostate cancer is the most commonly diagnosed cancer in the United States. Two major sequelae from the surgical management of prostate cancer are post-operative incontinence and erectile dysfunction (ED). Urinary incontinence following radical prostatectomy (RP) has been greatly reduced; however, neurogenic-ED following "nerve-sparing" RP persists. 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 following RP and thus maximizing postoperative erectile function outcomes. The experiments proposed in this application combine molecular biologic and neuroanatomic investigation of RhoA/ROCK signaling in the cavernous nerve with in vivo neurophysiological studies. We hypothesize that degeneration and neuronal cell apoptosis is a result of increased expression/activity of RhoA/ROCK in the major pelvic ganglion after cavernous nerve injury. Physiologic studies of selective RhoA and ROCK inhibitors effects in the context of neuroregulated erectile function and axonal regeneration are proposed after cavernous nerve injury. An understanding of the detrimental effects of RhoA/ROCK signaling in the cavernous nerve after injury and its influence on physiology of penile nerve function and repair can be expected to advance therapeutic strategies for ED particularly those related to nerve injury as well as other peripheral nerve neuropathies. I obtained my MD/PhD from Tulane University in Molecular Pharmacology. My PhD thesis focused on the influence of systemic disease states such as diabetes on endothelial cell biology, as it relates to cardiovascular disease and genitourinary tract function. During my urology training at Johns Hopkins, I was awarded a MD/PhD Fellowship from the American Urological Association Foundation to study the pathophysiology of endothelial cell dysfunction in sickle cell disease-associated priapism. During my residency and post-doctoral fellowship, I gained invaluable experience in both clinical and basic science investigations focusing on identifying a problem and linking molecular and pathological events which propagate disease initiation and progression. My career development award will focus on furthering my education about identifying putative molecular mechanisms of disease and thus design new disease-specific pharmacotherapies for the prevention and treatment of genitourinary tract disorders. More importantly, it will allow me to gain additional expertise in a new research area and significantly enhance my research capabilities in an effort to gain experience and mentorship that will lead to an independent and productive research career. The K08 award will afford me a significant block of protected time to devote to my research program. For a clinically active scientist the importance of this protection cannot be over-emphasized. The demands of patient care are difficult to predict and ever-expanding. Furthermore, while many early career grants cover 2 or 3 years, the K08 covers 5 years. The longer award period enhances my ability as an investigator to perform in-depth and rigorous study of a problem. The Brady Urological Institute is ideally suited to allow me to become an independent surgeon/scientist in Urology. Johns Hopkins has a rich history of training independent scientists and has all the resources necessary to carry out the proposed studies in my K08 grant. My mentor, Dr. Arthur Burnett, is a NIH supported investigator and is ideally suited to navigate my career development and provide me with career advice while helping me balance an active research lab and clinical practice. My goal over the next five year period is to obtain the best mentorship possible to succeed as an independent surgeon scientist integrating the fields of neuroscience, cell signaling, and neurobiology of disease pathogenesis. I hope to develop a research program focused on the identification and characterization of novel pathways involved in the promotion of axonal regeneration in response to nerve injury. I have proposed a series of experiments that utilize an animal model of cavernous nerve injury which is an established model to study the pathophysiology of post-radical prostatectomy ED. My career development award training goals include: 1. Understanding the molecular basis of peripheral nervous system function including neural development, synaptic transmission, and neuropathology; 2. Understanding the fundamental anatomical organization and histology of the axon and Schwann cell components of a nerve cell. Additionally acquire the skills to identify and differentiate the various states of normal, injured, and regenerating nerve cells; and 3. Improve my understanding of genetics and complement this with studies focused on gene expression profiling and bioinformatics as it relates to disease pathobiology. The invaluable education I will receive would allow me to understand the pathophysiology of axonal injury and allow me to design disease-specific molecular-based therapies to preserve lower urinary tract function. My long term career goals include obtaining additional NIH funding in the R-series and hopefully have the opportunity to participate in program project grants which combine a multi-disciplinary approach to genitourinary disease processes. I hope to one day mentor other young surgeon/scientist and provide them with the means and opportunity that my department and K08 funding will afford me.

描述(由申请人提供)：我建议的临床科学家导师研究职业发展奖(K08)将专注于一个具有巨大潜力影响神经病学领域的研究主题。前列腺癌是美国最常见的确诊癌症。前列腺癌手术治疗的两大后遗症是术后大小便失禁和勃起功能障碍。根治性前列腺切除术(RP)后的尿失禁已大大减少；然而，保留神经的RP后神经源性ED仍然存在。神经病学领域的进展主要集中在制定和实施策略，以保留阴茎勃起的神经基础和海绵体神经在RP术后的功能完整性，从而最大化术后勃起功能的结果。本申请中提出的实验将海绵体神经中RhoA/ROCK信号的分子生物学和神经解剖学研究与体内神经生理学研究相结合。我们推测，变性和神经细胞凋亡是海绵体神经损伤后盆腔大神经节RhoA/ROCK表达/活性增加的结果。海绵体神经损伤后，对选择性RhoA和ROCK抑制剂在神经调节勃起功能和轴突再生方面的作用进行了生理学研究。了解损伤后海绵体神经中RhoA/ROCK信号的有害作用及其对阴茎神经功能和修复生理的影响，有望促进勃起功能障碍的治疗，特别是与神经损伤和其他周围神经疾病相关的治疗策略。我在杜兰大学分子药理学专业获得了医学博士学位。我的博士论文关注的是糖尿病等系统性疾病状态对血管内皮细胞生物学的影响，因为它与心血管疾病和生殖道功能有关。在约翰·霍普金斯大学接受泌尿外科培训期间，我获得了美国泌尿协会基金会的医学/博士奖学金，研究镰状细胞疾病相关异常勃起的内皮细胞功能障碍的病理生理学。在我的住院医师和博士后研究期间，我在临床和基础科学研究方面获得了宝贵的经验，重点是识别问题并将传播疾病启动和发展的分子和病理事件联系起来。我的职业发展奖将集中在深化我的教育，识别可能的疾病分子机制，从而设计新的针对疾病的药物疗法来预防和治疗生殖泌尿系统疾病。更重要的是，这将使我在一个新的研究领域获得更多的专业知识，并显著增强我的研究能力，努力获得经验和指导，从而导致独立和富有成效的研究生涯。K08奖将为我提供大量受保护的时间来致力于我的研究计划。对于一名临床活跃的科学家来说，这种保护的重要性怎么强调都不为过。病人护理的需求很难预测，而且还在不断扩大。此外，虽然许多早期职业资助金的期限为2年或3年，但K08的期限为5年。较长的获奖期增强了我作为研究人员对问题进行深入和严格研究的能力。布雷迪泌尿研究所非常适合让我成为一名独立的泌尿外科医生/科学家。约翰斯·霍普金斯大学在培养独立科学家方面有着丰富的历史，拥有开展我的K08资助中提议的研究所需的所有资源。我的导师Arthur Burnett博士是NIH支持的研究员，他非常适合引导我的职业发展，为我提供职业建议，同时帮助我平衡积极的研究实验室和临床实践。在接下来的五年里，我的目标是获得尽可能好的指导，成为一名成功的独立外科科学家，整合神经科学、细胞信号和疾病发病机制的神经生物学领域。我希望开发一个研究计划，专注于识别和表征参与促进轴突再生的新途径，以应对神经损伤。我已经提出了一系列实验，利用海绵体神经损伤的动物模型来研究前列腺癌根治术后ED的病理生理学。我的职业发展奖培训目标包括：1.了解周围神经系统功能的分子基础，包括神经发育、突触传递和神经病理学；2.了解神经细胞轴突和雪旺细胞成分的基本解剖学组织和组织学。另外，学习识别和区分正常、受损和再生神经细胞的各种状态的技能；以及3.提高我对遗传学的理解，并以与疾病病理生物学相关的基因表达谱和生物信息学为重点的研究来补充这一点。我将接受的宝贵教育将使我了解轴突损伤的病理生理学，并使我能够设计针对疾病的分子疗法来保护下尿路功能。我的长期职业目标包括在R系列中获得更多的NIH资金，并希望有机会参与项目项目拨款，该项目将多学科方法结合到泌尿生殖系统疾病过程中。我希望有一天能指导其他年轻的外科医生/科学家，并为他们提供我的部门和K08基金将为我提供的手段和机会。