TRPC6 Regulation and its Role in Glomerular Pathology

TRPC6 调节及其在肾小球病理学中的作用

• 批准号: 8321104
• 负责人: JOHANNES S SCHLONDORFF
• 金额: $ 15.04万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8321104
• 关键词: Address; Animal Model; Animals; Area; Basement membrane; Binding; Biology; Calcineurin; Calcium; Cations; Cell-Matrix Junction; Cells; Cellular biology; Cytoskeletal Proteins; Data; Development; Dialysis procedure; Disease; End stage renal failure; Endothelial Cells; Experimental Designs; Family; Fellowship; Focal Segmental Glomerulosclerosis; Functional disorder; Gene Expression; Generations; Genes; Genetic Transcription; Goals; Health; Heart Hypertrophy; Human; Hypertrophic Cardiomyopathy; Hypertrophy; Image; Immunohistochemistry; In Vitro; Inherited; Ion Channel; Kidney; Kidney Diseases; Kidney Transplantation; Laboratories; Lead; Lesion; Mediating; Mediator of activation protein; Membrane; Methods; Modeling; Monitor; Mus; Mutation; NFAT Pathway; NPHS2 protein; Pathologic; Pathology; Pathway interactions; Postdoctoral Fellow; Process; Protein Isoforms; Proteins; Proteinuria; Regulation; Relative (related person); Renal glomerular disease; Research; Research Personnel; Role; Screening procedure; Signal Pathway; Signal Transduction; Site; System; Techniques; Technology; Therapeutic Intervention; Training; Transcriptional Activation; Transgenic Animals; Transgenic Mice; Urine; Work; base; cell type; diabetic; effective therapy; experience; gain of function; glomerular function; in vivo; insight; kidney cortex; medical schools; member; mutant; nephrin; novel; overexpression; patient population; podocyte; pressure; programs; slit diaphragm; transcription factor

DESCRIPTION (provided by applicant): Mutations in TRPC6, a nonspecific cation channel, have been found to lead to hereditary forms of focal segmental glomerulosclerosis. This project aims to define the role of TRPC6 in normal and abnormal glomerular function, with the goal of identifying the critical signaling pathways influenced by TRPC6. To this end, the candidate will: 1) characterize the mechanism whereby a subset of disease-associated mutations enhance TRPC6 channel activity; 2) assess the relative importance of abnormal TRPC6 function within various cell types within the glomerulus; and 3) establish the potential role of the NFAT transcription factor family as a target of TRPC6 signaling in the glomerulus. The candidate has past experience in a host of basic cell biology methods. In addition, during his post-doctoral fellowship training in Dr. Pollak's lab he has begun to develop an understanding of the techniques and experimental design required for studying channel biology, transcriptional activation, and for developing urine models of kidney disease. He has generated considerable preliminary data pertinent to the project. During his proposed project period, Dr. Schlondorff will be able to master several new techniques, including methods of intracellular calcium imaging, Cre-Lox transgenic animal generation, analysis of murine renal pathology, immunohistochemistry, and microarray gene expression technology. In addition to skilled members of the Pollak laboratory, Dr. Schlondorff has garnered the cooperation of several accomplished experts at the Harvard Medical School to assist him in these areas of development. PUBLIC HEALTH RELEVANCE: Focal segmental glomerular sclerosis (FSGS) is a kidney lesion seen in a number of disease states, contributes significantly to the population of patients with end-stage renal disease requiring dialysis or kidney transplantation, and currently lacks effective therapies. By gaining a better understanding of how genetic defects in an ion channel can lead to this disease, this project hopes to identify critical processes whose disruption lead to FSGS and kidney dysfunction in multiple forms of kidney disease. Our goal is that these insights will identify novel potential targets against which to develop therapeutic interventions.

描述（由申请人提供）： TRPC6中的突变（一种非特异性阳离子通道）已被发现导致遗传性形式的局灶性节段性肾小球硬化。该项目旨在定义TRPC6在正常和异常肾小球功能中的作用，以确定受TRPC6影响的临界信号通路。为此，候选人将：1）表征与疾病相关突变的子集增强TRPC6通道活性的机制； 2）评估肾小球内各种细胞类型中异常TRPC6功能的相对重要性； 3）确定NFAT转录因子家族作为肾小球中TRPC6信号的目标的潜在作用。候选人在许多基本细胞生物学方法中都有过去的经验。此外，在Pollak博士实验室的博士后奖学金培训期间，他已经开始了解研究通道生物学，转录激活以及开发肾脏疾病尿液模型所需的技术和实验设计。他产生了与该项目相关的大量初步数据。在他提议的项目期间，Schlondorff博士将能够掌握几种新技术，包括细胞内钙成像的方法，CRE-LOX转基因动物产生，鼠肾脏病理学分析，免疫组织化学和微阵列基因表达技术。除了熟练的Pollak实验室成员外，Schlondorff博士还获得了哈佛医学院的几位有成就的专家的合作，以帮助他在这些发展领域。 公共卫生相关性：局灶性节段性肾小球硬化症（FSG）是在许多疾病状态下看到的肾脏病变，对需要透析或肾脏移植的终末期肾脏疾病患者的人群产生了重大贡献，目前缺乏有效的治疗方法。通过更好地了解离子通道中的遗传缺陷如何导致这种疾病，该项目希望确定其破坏导致FSG和肾功能障碍多种形式的肾脏疾病的关键过程。我们的目标是，这些见解将确定开发治疗干预措施的新型潜在目标。

项目成果

GLCCI1 single nucleotide polymorphisms in pediatric nephrotic syndrome.

• DOI: 10.1007/s00467-012-2197-6
• 发表时间: 2012-09
• 期刊: PEDIATRIC NEPHROLOGY
• 影响因子: 3
• 作者: Cheong, Hae Il;Kang, Hee Gyung;Schlondorff, Johannes
• 通讯作者: Schlondorff, Johannes

Antagonistic regulation of actin dynamics and cell motility by TRPC5 and TRPC6 channels.

• DOI: 10.1126/scisignal.2001200
• 发表时间: 2010-10-26
• 期刊: Science signaling
• 影响因子: 7.3
• 作者: Tian D;Jacobo SM;Billing D;Rozkalne A;Gage SD;Anagnostou T;Pavenstädt H;Hsu HH;Schlondorff J;Ramos A;Greka A
• 通讯作者: Greka A