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Illuminating the role of chloride channel regulator CLCA4 in TMEM16 Family potentiation and disease

阐明氯离子通道调节剂 CLCA4 在 TMEM16 家族增强和疾病中的作用

基本信息

批准号：
10217542
负责人：
THOMAS John BRETT
金额：
$ 15.75万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-15 至 2023-05-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10217542
关键词：
Airway Disease Anions Antibodies Asthma Binding Biochemical Biological Biological Process Brain Calcium Cell Culture Techniques Cells Chemosensitization Chloride Channels Chlorides Chronic Obstructive Airway Disease Cleaved cell Crohn&apos s disease Cystic Fibrosis Data Diarrhea Digestive System Disorders Disease Drug Targeting Electrophysiology (science)Enzyme-Linked Immunosorbent Assay Family Family member Future Gastrointestinal Diseases Gastrointestinal tract structure Genetic Goals Health Human Inflammatory Intestines Knowledge Literature Lung Lung diseases Malignant Neoplasms Metalloproteases Molecular Monoclonal Antibodies Mucous Membrane Pattern Pilot Projects Play Protein Family Proteins Reagent Regulation Research Role Sampling Stains Structure Surface System Tissues Ulcerative Colitis base experimental study knowledge base mRNA Expression member novel targeted treatment tool

项目摘要

ABSTRACT: The calcium-activated chloride channel regulator CLCA4 has been associated with and suggested as a drug target for inflammatory diseases of the airway and gastrointestinal tract including asthma, COPD, cystic fibrosis, infectious diarrhea, Crohn's disease, ulcerative colitis, and some cancers. However, a detailed understanding of its biological functions has lagged far behind its association with these diseases, largely due to complete lack of biochemical knowledge and quality antibody reagents. We recently made groundbreaking advances investigating a related family member, CLCA1, by showing that it is a self-cleaving metalloprotease that binds to and potentiates the calcium activated chloride channel TMEM16A. In our preliminary data we show that CLCA4 acts in a similar manner on another distinct TMEM16 family member, TMEM16B. Therefore, we are uniquely poised to generate significant advances in our understanding of CLCA4 function in health and disease. This pilot project will develop the knowledge base and tools required to facilitate this. In Aim 1, we will investigate the mechanism of regulation of CLCA4 activity and comprehensively validate that TMEM16B is the sole TMEM16 family member modulated by CLCA4. In Aim 2, we will develop a novel panel of monoclonal antibody reagents specific for the mature, cleaved forms of CLCA4 (N-CLCA4 and C-CLCA4) that can be used in several experimental formats, and carry out initial analysis of healthy and diseased airway and intestinal tissue and biological samples with them. The long-term goal of this project (beyond this pilot R03) is to develop a comprehensive mechanistic understanding of CLCA4 function in health and disease, which we believe is sorely underappreciated. Successful completion of this pilot will provide the knowledge and tools to investigate the functional roles of CLCA4 in specific diseases and to develop targeted therapeutics in subsequent projects.

摘要：钙激活的氯离子通道调节剂CLCA 4已被认为与作为气道和胃肠道炎性疾病的药物靶点，包括哮喘、COPD、囊性纤维化、感染性腹泻、克罗恩病、溃疡性结肠炎和一些癌症。然而，详细的对它的生物学功能的了解远远落后于它与这些疾病的联系，这主要是由于完全缺乏生化知识和优质抗体试剂。我们最近做出了突破性的研究相关家族成员CLCA 1的进展，表明它是一种自我切割的金属蛋白酶其结合并增强钙激活的氯离子通道TMEM 16 A。在我们的初步数据中，显示CLCA 4以类似的方式作用于另一个不同的TMEM 16家族成员TMEM 16 B。因此，我们认为，我们将在对CLCA 4在健康中的功能的理解方面取得重大进展，疾病这一试点项目将发展促进这一工作所需的知识库和工具。在目标1中，我们研究CLCA 4活性的调控机制，全面验证TMEM 16 B是CLCA 4的活性调控基因，唯一由CLCA 4调节的TMEM 16家族成员。在目标2中，我们将开发一种新的单克隆抗体，可以使用的对成熟的、裂解形式的CLCA 4（N-CLCA 4和C-CLCA 4）特异的抗体试剂在几个实验格式，并进行初步分析，健康和患病的气道和肠道组织和生物样本本项目的长期目标（超出本试验R 03）是开发对CLCA 4在健康和疾病中功能的全面机制理解，我们认为这是被严重低估了成功完成这一试点将提供知识和工具， CLCA 4在特定疾病中的功能作用，并在后续项目中开发靶向治疗药物。