LPA2 receptor-containing complexes in regulating secretory diarrhea

含 LPA2 受体的复合物调节分泌性腹泻

基本信息

批准号：
8698411
负责人：
Anjaparavanda P Naren
金额：
$ 30.54万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-15 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8698411
关键词：
Acute Affect Agonist Animal Model Apical Cell Line Cell membrane Cells Cessation of life Childhood Chloride Channels Chloride Ion Chlorides Cholera Cholera Toxin Complex Coupled Cyclic AMP Cystic Fibrosis Transmembrane Conductance Regulator Diarrhea Disease Edg4 Protein Elderly Electrolytes Epithelial Cells Event Exocrine Glands Fluids and Secretions Generations Hospitalization Human Incidence Inflammatory Bowel Diseases Intestines Knockout Mice Lysophosphatidic Acid Receptors Macromolecular Complexes Mediating Modeling Molecular Multiprotein Complexes Mus Physicians Physiological Play Population Process Regulation Research Role Signal Pathway Signal Transduction Sodium Chloride Surface Testing Therapeutic Intervention United States Visit Water attenuation gastrointestinal epithelium in vivo innovation mouse model protein protein interaction receptor expression receptor-mediated signaling response small hairpin RNA sodium-hydrogen exchanger regulatory factor technology/technique development

项目摘要

DESCRIPTION (provided by applicant): The unifying hypothesis of this proposal is that macromolecular complex of type 2 lysophosphatidic acid receptor (LPA2 receptor) and Na+/H+ exchange regulatory factor-2 (NHERF2) plays important roles in the pathogenic process of secretory diarrhea. We aim to study the formation and regulation of the macromolecular complex at the molecular level under physiological and pathophysiological conditions that play a critical role in cholera induced diarrhea. Moreover, the research will study the mechanism through which LPA2 receptor- mediated signaling events regulate CFTR-dependent electrolyte secretion in cells and fluid secretion in an animal model of diarrhea. Three aims will be studied: Aim 1: To test the hypothesis that LPA2 receptor is primarily expressed on the luminal surface of the gut and is down regulated in certain forms of diarrheal diseases, and to test the hypothesis that activation of LPA2 receptor inhibits compartmentalized cAMP generation at the plasma membrane. Aim 2: To test the hypothesis that LPA can regulate the formation of the LPA2-containing macromolecular complex by further clustering it to microdomain on the plasma membrane and that the process is mediated by NHERF2-dependent protein-protein interactions Aim 3: To test the hypothesis that disruption of the macromolecular complex by silencing NHERF2 alters compartmentalized cAMP levels at the plasma membrane and that in vivo NHERF2 knockout mice generate altered cAMP in response to CTX. The proposal is of great importance and significance for understanding the pathogenic process of the deadly secretory diarrheal diseases at the molecular level, and for possible therapeutic intervention of the disease. The proposed study is highly innovative in both conceptual advance and in technology/technique development.

描述（由申请人提供）：该提案的统一假设是2型溶血磷脂受体（LPA2受体）和Na+/H+交换调控因子2（NHERF2）的大分子复合物在秘密腹泻的致病过程中起着重要作用。我们旨在研究生理和病理生理条件下分子水平上大分子复合物的形成和调节，在霍乱诱导的腹泻中起着关键作用。此外，该研究将研究LPA2受体介导的信号事件通过细胞中CFTR依赖的电解质分泌的机制和腹泻动物模型中的液体分泌。将研究三个目的：目标1：测试LPA2受体主要在肠道表面表达的假设，并以某些形式的腹泻疾病调节，并测试以下假设，即LPA2受体的激活在Plasmambrane plasmambrane cancmentalizatizan camp Membrane的cAMP产生。目的2：测试LPA可以通过将其进一步聚集到质膜上的微分域来调节含LPA2的大分子复合物的形成的假设，并且该过程是由NHERF2依赖性蛋白质 - 蛋白质相互作用介导的，目的是在测试隔离阶级的隔离层的隔离层构造nherf2依赖性的蛋白质相互作用。质膜和体内NHERF2敲除小鼠对CTX的响应会改变cAMP。该提案对于理解分子水平上致命分泌性腹泻疾病的致病过程以及可能对疾病的治疗干预措施非常重要和重要性。拟议的研究在概念进步和技术/技术开发中都具有很高的创新性。