Spatial and Temporal Induction of Calcineurin in the Urinary Bladder

膀胱中钙调神经磷酸酶的空间和时间诱导

基本信息

批准号：
8368449
负责人：
Stephen Anthony Zderic
金额：
$ 21.95万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-03 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8368449
关键词：
Agonist Anatomy Applications Grants Binding Bladder Blood Vessels Breeding Calcineurin Calcineurin Pathway Calcineurin inhibitor Calmodulin Cardiac Catalytic Domain Cell Communication Cell Nucleus Cells Cellular Stress Chronic Cleaved cell Clinical Complex Coupled Cyclosporine Development Dose Doxycycline Elements Event Family Gene Expression Hypertrophy Immunosuppressive Agents Individual Institutes Lung Maps Mechanics Mediating Memory Modeling Mus Nature Obstruction Outcome Measure Partner in relationship Pathway interactions Patients Pharmaceutical Preparations Phenotype Phosphoric Monoester Hydrolases Play Population Positioning Attribute Protein Isoforms Proteins Quality of life Reagent Response Elements Role Signal Transduction Site Smooth Muscle Smooth Muscle Myocytes Spinal Dysraphism Spinal cord injury Staging Stimulus Stretching Surgical Models System The Jackson Laboratory Trans-Activators Transgenic Mice Transgenic Organisms Urothelium base calcineurin phosphatase cell type connective tissue growth factor drinking water human MYH11 protein improved inhibitor/antagonist interest lymphocyte proliferation molecular mass nerve injury novel strategies nuclear factors of activated T-cells offspring prevent promoter relating to nervous system research study response social stress transcription factor uptake vector

Agonist Anatomy Applications Grants Binding Bladder Blood Vessels Breeding Calcineurin Calcineurin Pathway Calcineurin inhibitor Calmodulin Cardiac Catalytic Domain Cell Communication Cell Nucleus Cells Cellular Stress Chronic Cleaved cell Clinical Complex Coupled Cyclosporine Development Dose Doxycycline Elements Event Family Gene Expression Hypertrophy Immunosuppressive Agents Individual Institutes Lung Maps Mechanics Mediating Memory Modeling Mus Nature Obstruction Outcome Measure Partner in relationship Pathway interactions Patients Pharmaceutical Preparations Phenotype Phosphoric Monoester Hydrolases Play Population Positioning Attribute Protein Isoforms Proteins Quality of life Reagent Response Elements Role Signal Transduction Site Smooth Muscle Smooth Muscle Myocytes Spinal Dysraphism Spinal cord injury Staging Stimulus Stretching Surgical Models System The Jackson Laboratory Trans-Activators Transgenic Mice Transgenic Organisms Urothelium base calcineurin phosphatase cell type connective tissue growth factor drinking water human MYH11 protein improved inhibitor/antagonist interest lymphocyte proliferation molecular mass nerve injury novel strategies nuclear factors of activated T-cells offspring prevent promoter relating to nervous system research study response social stress transcription factor uptake vector

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项目摘要

DESCRIPTION (provided by applicant): We have shown that the calcineurin pathway is activated following partial Bladder Outlet Obstruction (pBOO), and that inhibition with its known inhibitor cyclosporine A (CSA) results in a more favorable bladder phenotype. Despite the benefits that surgical models offer, they do have limitations: 1) there is a variable degree of hypertrophy. 2) Multiple pathways are simultaneously activated with pBOO. 3) Multiple cell types exist within the bladder wall in which the pathway may or not be activated. 4) There is a potential for changes induced by the pathway of interest in one cell population to induce changes in another. Despite their benefits in a recapitulation of the events that take place in clinical pBOO, the nature of surgical models makes the study of individual pathways and cell to cell interactions very difficult. In order to more fully investigate the mechanism(s) by which calcineurin mediates bladder wall hypertrophy, we now propose the development of a transgenic strategy that allows us to turn on calcineurin under the control of the doxycycline sensitive promoter within the urothelium or the smooth muscle cell populations. This will allow for a more precise mechanistic assessment of the role this pathway plays in bladder wall hypertrophy following pBOO. In addition the reagent mouse that we generate in this proposal will find applicability in the study of other systems (such as cardiac, pulmonary, vascular, and neural) where the calcineurin pathway is active. PUBLIC HEALTH RELEVANCE: Bladder wall hypertrophy often develops in patients either as a result of an anatomic blockage or as a result of abnormal voiding due to nerve injury as seen patients spina bifida or spinal cord injury. We have shown that the calcineurin pathway is activated following partial outlet obstruction in the mouse. This grant proposal seeks to develop a more refined proof of concept using modern transgenic strategies that calcineurin helps mediate bladder wall hypertrophy. This model offers us and improved platform in which to demonstrate the potential benefit of using cyclopsorine A (a known calcineurin inhibitor) as a treatment to preserve bladder function. A strategy of preserving function and preventing the end stage bladder using pharmacologic manipulation that is instituted early will offer these patients an improved quality of life.

描述（由申请人提供）：我们已经表明，部分膀胱出口障碍物（PBOO）激活了钙调神经素途径，并且其已知的抑制剂环孢菌素A（CSA）抑制会导致更有利的膀胱表型。尽管手术模型提供了好处，但它们确实有局限性：1）肥大程度可变。 2）多种途径与PBOO同时激活。 3）在膀胱壁中存在多种细胞类型，该膀胱壁可能会被激活或不被激活。 4）在一个细胞种群中感兴趣的途径引起的变化有可能引起另一种细胞的变化。尽管它们在临床PBOO中发生的事件的概括中有好处，但手术模型的性质使研究单个途径和细胞与细胞相互作用的研究非常困难。为了更全面地研究钙调神经蛋白会介导膀胱壁肥大的机制，我们现在提出了转基因策略的发展，该策略使我们能够在尿皮细胞内强力霉素敏感的启动子或平滑肌细胞种群中打开钙调蛋白。这将允许对PBOO后这种途径在膀胱壁肥大中的作用进行更精确的机理评估。此外，我们在该提案中生成的试剂小鼠将在研究其他系统（例如心脏，肺，血管和神经）的研究中找到适用性，其中钙调神经素途径处于活动状态。公共卫生相关性：由于神经损伤而导致的异常缺失，患者经常会出现膀胱壁肥大，而患者如见证的患者Spina bifida或脊髓损伤。我们已经表明，在小鼠中部分出口障碍物后，激活了钙调神经素途径。该赠款提案旨在使用钙调神经酶有助于介导膀胱壁肥大的现代转基因策略来开发更精致的概念证明。该模型为我们提供了改进的平台，在该平台中，可以证明使用环虫A（已知的钙调神经酶抑制剂）作为保留膀胱功能的治疗方法的潜在优势。一种使用药理学操纵来保存功能并防止末期膀胱的策略，该操作会提早提早，将为这些患者提供改善的生活质量。