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: 8843417
• 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 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8843417
• 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 injury; axon regeneration; axonal degeneration; base; cancer diagnosis; cancer therapy; career; career development; cell motility; clinical practice; design; differential expression; experience; extracellular; genome-wide analysis; 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; spared nerve; 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）：我提议的指导临床科学家研究职业发展（K08）奖将重点关注对神经泌尿学领域具有巨大潜力的研究课题。前列腺癌是美国最常诊断的癌症。前列腺癌手术治疗的两个主要后遗症是术后失禁和勃起功能障碍（ED）。根治性前列腺切除术（RP）后的尿失禁已大大减少；然而，“神经保留”RP 后的神经源性 ED 仍然存在。神经泌尿学领域的进展集中在开发和实施策略，以保留阴茎勃起的神经源性基础和 RP 后海绵体神经的功能完整性，从而最大限度地提高术后勃起功能结果。本申请中提出的实验将海绵神经中 RhoA/ROCK 信号传导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。我们假设变性和神经元细胞凋亡是海绵体神经损伤后骨盆主要神经节中 RhoA/ROCK 表达/活性增加的结果。提出了海绵神经损伤后选择性 RhoA 和 ROCK 抑制剂在神经调节勃起功能和轴突再生中的作用的生理学研究。了解损伤后海绵体神经中 RhoA/ROCK 信号传导的有害影响及其对阴茎神经功能和修复生理学的影响有望推进 ED 的治疗策略，特别是与神经损伤以及其他周围神经神经病变相关的治疗策略。 我在杜兰大学获得了分子药理学医学博士/博士学位。我的博士论文重点关注糖尿病等全身性疾病状态对内皮细胞生物学的影响，因为它与心血管疾病和泌尿生殖道功能有关。在约翰·霍普金斯大学泌尿外科培训期间，我获得了美国泌尿外科协会基金会颁发的医学博士/博士学位奖学金，以研究镰状细胞病相关的阴茎异常勃起中内皮细胞功能障碍的病理生理学。在住院医师实习和博士后研究期间，我在临床和基础科学研究方面获得了宝贵的经验，重点是确定问题并将传播疾病发生和进展的分子和病​​理事件联系起来。我的职业发展奖将侧重于进一步深入了解疾病的假定分子机制，从而设计新的疾病特异性药物疗法来预防和治疗泌尿生殖道疾病。更重要的是，它将让我获得新研究领域的额外专业知识，并显着提高我的研究能力，以获得经验和指导，从而实现独立和富有成效的研究生涯。 K08 奖项将为我提供大量受保护的时间来投入我的研究项目。对于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。患者护理的需求难以预测并且不断扩大。此外，虽然许多早期职业补助金的期限为 2 或 3 年，但 K08 的期限为 5 年。较长的奖励期限增强了我作为研究者对问题进行深入和严格研究的能力。布雷迪泌尿外科研究所非常适合让我成为泌尿外科的独立外科医生/科学家。约翰·霍普金斯大学在培养独立科学家方面拥有丰富的历史，并且拥有开展我的 K08 资助中拟议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，非常适合指导我的职业发展并为我提供职业建议，同时帮助我平衡活跃的研究实验室和临床实践。 我未来五年的目标是获得尽可能最好的指导，作为一名独立的外科医生科学家，整合神经科学、细胞信号传导和疾病发病机制的神经生物学领域。我希望开发一个研究项目，重点是识别和表征参与促进轴突再生以应对神经损伤的新途径。我提出了一系列实验，利用海绵神经损伤的动物模型，这是研究根治性前列腺切除术后 ED 病理生理学的既定模型。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. 了解神经细胞的轴突和雪旺细胞成分的基本解剖结构和组织学。此外，还获得识别和区分正常、受损和再生神经细胞的各种状态的技能； 3. 提高我对遗传学的理解，并通过与疾病病理学相关的基因表达谱和生物信息学研究来补充这一点。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特定疾病的分子疗法以保护下尿路功能。我的长期职业目标包括获得 R 系列的额外 NIH 资助，并希望有机会参与结合多学科方法治疗泌尿生殖疾病过程的项目资助。我希望有一天能够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 资金将为我提供的手段和机会。