CFTR-Independent Bicarbonate Secretion is a Novel CF Therapeutic Target

不依赖 CFTR 的碳酸氢盐分泌是一种新型 CF 治疗靶点

• 批准号: 10356910
• 负责人: Zachary Michael Sellers
• 金额: $ 16.65万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10356910
• 关键词: 3-Dimensional; Advisory Committees; Affect; Award; Bicarbonates; Binding; Binding Proteins; Biotinylation; CRISPR/Cas technology; Cell membrane; Cell surface; Chloride-Bicarbonate Antiporters; Complement; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Defect; Disease; Down-Regulation; Duodenum; Effectiveness; Ensure; Enterotoxins; Environment; Escherichia coli; Genes; Genetic Diseases; Genotype; Goals; Human; Immunofluorescence Immunologic; In Vitro; Inositol; Intervention; Intestines; Investigation; Ion Channel; Ion Transport; Knock-out; Life; Malabsorption Syndromes; Measures; Mentors; Modeling; Morbidity - disease rate; Mus; Mutation; Nutrient; Organoids; Pancreatic enzyme; Pathogenesis; Pathway interactions; Patients; Pattern; Pediatrics; Persons; Pharmaceutical Preparations; Pharmacology; Phospholipase C; Physicians; Property; Regulation; Research; Research Personnel; Respiratory Failure; Role; SLC26A3 gene; Scientist; Signal Pathway; Site; Surface; Techniques; Technology; Therapeutic; Tissues; Titrations; Traction; Training; Translational Research; United States; Universities; VX-770; Villus; Western Blotting; Wine; analog; base; career development; cost; cystic fibrosis airway; cystic fibrosis patients; differential expression; enzyme activity; experience; experimental study; gastrointestinal; improved; inhibitor; instructor; medical schools; mortality; novel; novel therapeutics; pulmonary function; putative anion transporter 1; receptor binding; small molecule; success; therapeutic target; tool; tripolyphosphate

PROJECT SUMMARY This is an application for a K08 award for Dr. Sellers, an Instructor of Pediatrics at Stanford University School of Medicine. Dr. Sellers is researching ion transport in Cystic Fibrosis (CF) airway and intestine and wishes to establish himself as a young investigator in CF translational research. The K08 award for CF research on intestinal bicarbonate secretion will provide Dr. Sellers support to achieve the following goals for his career development: i) to establish patient derived 3-dimensional duodenal enteroids which recapitulate native CF duodenal tissue’s bicarbonate secretory properties, ii) to gain expertise in CRISPR/Cas9 editing techniques that can complement pharmacologic interventions to study ion transport, and iii) to gain experience in translational investigation into identifying new therapeutic modulators of duodenal bicarbonate secretion in CF. To oversee Dr. Sellers’ training, he will be mentored by Dr. Calvin Kuo, an established figure in in vitro organoid models. He will also be co-mentored by Dr. Jeffrey Wine, an expert in CF ion transport. Dr. Sellers has also formed an advisory team of Dr. Matthew Porteus, Dr. Eric Sibley, and Dr. Kim Barrett, who will complement the expertise of Dr. Sellers, Kuo, and Wine, and provide additional expert oversight for Dr. Sellers’ proposed research. Dr. Sellers has surrounded himself with a group of established investigators that will ensure his success. Cystic Fibrosis is the most common, life-shortening genetic disease, affecting approximately 30,000 persons in the U.S. and 100,000 persons worldwide. Lung failure remains the number one cause for mortality in CF, however, patients experience significant morbidity associated with gastrointestinal manifestations and these are known to contribute to the decline in pulmonary function. The importance of bicarbonate secretion through the cystic fibrosis transmembrane conductance regulator (CFTR) in CF has gained traction in recent years. There are newly developed drugs that improve CFTR expression and function, but there are no therapies aimed at specifically improving bicarbonate secretion, and as such an important therapeutic gap exists. To identify new ways to increase bicarbonate secretion in CF, Dr. Sellers will use developing technologies with 3-dimensional enteroid cultures and CRISPR/Cas9 editing to investigate cellular signaling pathways that promote bicarbonate transport. This project will close the gap on establishing a human-based model for investigating bicarbonate secretion in CF and will also utilize gene editing tools that can delineate signaling pathways where no specific pharmacologic tools exist. It is anticipated that this research plan will not only identify new therapeutic bicarbonate secretory pathways in CF, but together with the training plan, will enhance Dr. Sellers’ transition to independence as a physician-scientist in CF translational research.

项目摘要 这是一份K 08奖的申请书，申请人是斯坦福大学儿科学院的讲师Sellers博士。 药Sellers博士正在研究囊性纤维化（CF）气道和肠道中的离子转运，并希望 使自己成为CF转化研究的年轻研究员。CF研究的K 08奖 肠道碳酸氢盐分泌将为Sellers博士的职业生涯提供以下目标 开发：i）建立患者来源的三维十二指肠肠样结构，其重现天然CF 十二指肠组织的碳酸氢盐分泌特性，ii）获得CRISPR/Cas9编辑技术的专业知识， 可以补充药理学干预研究离子转运，和iii）获得翻译经验， 鉴定CF中十二指肠碳酸氢盐分泌的新治疗调节剂的研究。监督 博士塞勒斯的培训，他将指导博士卡尔文郭，一个既定的数字在体外类器官模型。他 也将共同指导博士杰弗里葡萄酒，在CF离子传输专家。塞勒斯博士还成立了一个 Matthew Porteus博士，Eric Sibley博士和Kim Barrett博士的顾问团队，他们将补充专业知识 Sellers博士、Kuo博士和Wine博士，并为Sellers博士提出的研究提供额外的专家监督。博士 塞勒斯身边有一群老牌的调查人员，这将确保他的成功。 囊性纤维化是最常见的缩短寿命的遗传性疾病，在美国约有30，000人受到影响。 美国和全世界10万人。肺衰竭仍然是CF死亡的头号原因， 然而，患者经历与胃肠道表现相关的显著发病率， 导致肺功能下降碳酸氢盐分泌的重要性通过 近年来，囊性纤维化跨膜传导调节因子（CFTR）在囊性纤维化中的作用越来越受到关注。那里 是新开发的改善CFTR表达和功能的药物，但目前还没有针对CFTR的治疗方法。 特别是改善碳酸氢盐分泌，因此存在重要的治疗空白。 为了确定增加CF中碳酸氢盐分泌的新方法，Sellers博士将使用开发中的技术， 3-三维肠样培养和CRISPR/Cas9编辑来研究细胞信号传导途径， 促进碳酸氢盐运输。该项目将缩小建立以人为本的模型的差距， 研究CF中的碳酸氢盐分泌，还将利用基因编辑工具， 没有特定药理学工具存在的途径。预计这项研究计划不仅将确定 新的治疗性碳酸氢盐分泌途径在CF，但与培训计划一起，将提高博士。 塞勒斯在CF转化研究中作为一名医生-科学家向独立的过渡。