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）：我们已经证明，钙调磷酸酶途径在部分膀胱出口梗阻（pBOO）后被激活，并且用其已知抑制剂环孢菌素A（CSA）进行抑制会产生更有利的膀胱表型。尽管手术模型提供了好处，但它们确实有局限性：1）存在不同程度的肥大。2)pBOO可同时激活多种途径。3)膀胱壁内存在多种细胞类型，其中该途径可能被激活或不被激活。4)在一个细胞群中由感兴趣的途径诱导的变化有可能诱导另一个细胞群的变化。尽管它们在临床pBOO中发生的事件的重演中具有益处，但手术模型的性质使得个体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磷酸酶介导膀胱壁肥大的机制，我们现在提出了一种转基因策略的发展，该策略允许我们在尿道或平滑肌细胞群内的强力霉素敏感启动子的控制下打开钙调磷酸酶。这将允许对该途径在pBOO后膀胱壁肥大中所起的作用进行更精确的机制评估。此外，我们在本提案中产生的试剂小鼠将在钙调磷酸酶通路活跃的其他系统（如心脏、肺、血管和神经）的研究中找到适用性。