CFTR-Independent Bicarbonate Secretion is a Novel CF Therapeutic Target

项目总结 这是Sellers博士的K08奖项的申请表，他是斯坦福大学医学院的儿科学讲师 医学。塞勒斯博士正在研究囊性纤维化(CF)呼吸道和肠道中的离子传输，并希望 在翻译研究中确立自己作为一名年轻的研究员的地位。Cf研究K08奖 肠道碳酸氢盐分泌物将为Sellers博士提供支持，以实现他职业生涯的以下目标 开发：i)建立患者来源的三维十二指肠小肠样体，概括天然的CFs 十二指肠组织的碳酸氢盐分泌特性，ii)获得CRISPR/Cas9编辑技术方面的专业知识， 可以补充药物干预以研究离子转运，以及iii)获得翻译方面的经验 寻找新的十二指肠碳酸氢盐分泌治疗调节剂的研究监督 在Sellers博士的培训之后，他将得到Calvin Kuo博士的指导，Calvin Kuo博士是体外有机模型领域的知名人物。他 还将由CF离子传输专家Jeffrey Wine博士共同指导。塞勒斯博士还形成了一个 Matthew Porteus博士、Eric Sibley博士和Kim Barrett博士组成的顾问团队，他们将补充专业知识 Sellers博士、Kuo博士和Wine博士，并为Sellers博士提议的研究提供额外的专家监督。Dr。 塞勒斯身边有一群老牌调查人员，他们将确保他的成功。 囊性纤维化是最常见的、缩短寿命的遗传病，在美国约有30,000人患病 美国和全球10万人口。肺功能衰竭仍然是CF死亡的头号原因， 然而，患者会经历与胃肠道症状相关的显著发病率，这些症状包括 已知会导致肺功能下降。小苏打分泌的重要性通过 近年来，囊性纤维化跨膜电导调节因子(CFTR)在CF中得到了广泛的应用。那里 是新近开发的可以改善CFTR表达和功能的药物，但目前还没有针对 特别是改善碳酸氢盐的分泌，因此存在着一个重要的治疗缺口。 为了确定增加CF中碳酸氢盐分泌的新方法，塞勒斯博士将使用正在开发的技术 三维肠样培养和CRISPR/Cas9编辑以研究细胞信号通路 促进碳酸氢盐运输。该项目将缩小在建立以人为本的模型方面的差距 研究CF中的碳酸氢盐分泌，并将利用可以描绘信号的基因编辑工具 不存在特定药理工具的路径。预计这项研究计划不仅将确定 在CF中，新的治疗碳酸氢盐分泌途径，但与训练计划一起，将增强DR。 赛勒斯在翻译研究方面作为一名内科科学家向独立的过渡。

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.