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

• 批准号: 8521409
• 负责人: Stephen Anthony Zderic
• 金额: $ 24.39万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 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/8521409
• 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

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.

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。