Submucosal esophageal structures as a progenitor niche for esophageal repair

粘膜下食管结构作为食管修复的祖细胞生态位

• 批准号: 9250126
• 负责人: Katherine Garman
• 金额: $ 13.94万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9250126
• 关键词: Acute; Advisory Committees; Animal Model; Animals; Barrett Esophagus; Basic Science; Biology; Cavia; Cell Culture Techniques; Cells; Cellular biology; Chronic; Clinical Research; Columnar Cell; Curiosities; Data; Development; Diagnosis; Disease; Duct (organ) structure; Early Diagnosis; Endoscopy; Epithelial; Epithelium; Erinaceidae; Esophageal; Esophageal Adenocarcinoma; Esophageal Diseases; Esophageal injury; Esophagus; Event; Family suidae; Fibroblasts; Foundations; Gastroesophageal reflux disease; Gastrointestinal Injury; Gastrointestinal tract structure; Gland; Goals; Human; In Vitro; Incidence; Injury; Institution; Internal Medicine; Intestines; Laboratories; Lead; Lesion; Malignant neoplasm of esophagus; Mentors; Metaplastic; Microarray Analysis; Modeling; Molecular; Mus; Obesity; Organ; Organoids; Outcomes Research; Pathway interactions; Patients; Play; Population; Premalignant; Prevention strategy; Process; Proliferating; Publications; Reflux; Research; Research Personnel; Research Project Grants; Risk Factors; Risk stratification; Rodent Model; Role; Sampling; Signal Transduction; Skin; Sorting - Cell Movement; Squamous Cell; Squamous Epithelium; Stem cells; Stratum Basale; Structure; Submucosa; System; Teacher Professional Development; Techniques; Time; Training; Translating; Work; base; biomarker development; carcinogenesis; career development; clinical risk; esophageal cancer prevention; esophageal gland; gastrointestinal; high risk; human tissue; improved; injured; injury and repair; interest; male; mortality; notch protein; progenitor; public health relevance; repaired; response; screening; sex; skills; skills training; stem cell biology; surveillance strategy; yearning

DESCRIPTION (provided by applicant): In my training thus far, I have successfully completed several clinical and outcomes research projects, resulting in publications. Yet during my year as the Chief Resident in internal medicine at Duke, the unexpected began to happen: I became increasingly interested in basic research questions. Because we seemed unable to positively impact the rate of esophageal cancer development, my curiosity grew about the molecular events behind pre-malignant disease in the gastrointestinal tract. I began to consider how a better understanding of the basic esophageal biology might translate into much needed advances in patient screening, surveillance and risk-stratification. This yearning for deeper biologic understanding has driven the formation of the proposed project and mentoring team. Esophageal cancer has a five-year survival of less than 17%, and esophageal adenocarcinoma (EAC) now comprises more than 50% of esophageal cancer cases. Current screening efforts have failed to impact mortality. In order to improve survival, new strategies for prevention and early detection are needed. The squamous progenitor cells in the basal layer of the esophageal squamous epithelium and at the squamo-columnar junction have been extensively studied. In humans, progenitors for high-risk BE and EAC may be different (perhaps less differentiated) than the basal squamous epithelial progenitor, and this human esophageal progenitor may be located deeper in the submucosa than the cells found at the squamo-columnar junction in mice. Such progenitors may have potential to give rise to both basal squamous and columnar cells (as in BE), with the fate of its differentiated progeny determined by signals generated when repair is required. There may also be differences in progenitors based upon species. The normal human esophagus contains submucosal glands and ducts (ESMG/ESMD). Traditional rodent models are limited in that they lack the esophageal glands and ducts found in humans. As a consequence, these animals are not adequate for modeling the potential role of submucosal progenitor cells in the initiation of BE and EAC. Here I propose to develop a small animal model (guinea pig) to further our understanding of the role of submucosal progenitor cells in esophageal injury and repair, as well as a large animal (pig) based system of ESMG/ESMD isolation and culture. This project will serve as a training vehicle as well as a platform for my long term goal of studying these cells in the development of BE and EAC. In order to accomplish my long-term goal to improve early-detection of high-risk human esophageal disease and impact mortality associated with esophageal adenocarcinoma (EAC), I seek further career development in order to attain skills in epithelial biology, gastrointestinal stem cell biology, and animal models of esophageal injury and repair. Duke is a well-established research institution, with a clear commitment to supporting junior faculty development. I have already been provided independent laboratory space and 75% protected research time. I am fortunate to have a very strong mentoring team and research advisory committee to help facilitate my transition over the next few years to become an independent investigator with a strong skill-set in basic science techniques that will be developed through the proposed work. This project will be mentored by Dr. Anna Mae Diehl, an expert in cell biology and molecular pathways in gastrointestinal injury and repair, and it will be co-mentored by Dr. Susan Henning, an expert in intestinal stem cell biology. Experts in esophageal biology, animal models of esophageal disease, and epithelial repair will provide additional support and skills training.

描述(由申请者提供)：在我的培训中，到目前为止，我已经成功地完成了几个临床和结果研究项目，并发表了论文。然而，在我担任杜克大学内科首席住院医师的这一年里，意想不到的事情开始发生：我对基础研究问题越来越感兴趣。由于我们似乎无法积极影响食道癌的发展速度，我对胃肠道癌前疾病背后的分子事件产生了越来越大的好奇心。我开始考虑如何将对基本食道生物学的更好理解转化为在患者筛查、监测和风险分层方面亟需的进展。这种对更深层次生物理解的渴望推动了拟议的项目和指导团队的形成。食道癌的五年生存率不到17%，食管腺癌(EAC)目前占食道癌病例的50%以上。目前的筛查努力未能影响死亡率。为了提高存活率，需要制定新的预防和早期发现战略。食道鳞状上皮基底层和鳞状柱状交界处的鳞状前体细胞已被广泛研究。在人类中，高危BE和EAC的祖细胞可能与基本的鳞状上皮祖细胞不同(可能分化较少)，并且这种人类食管祖细胞可能比小鼠鳞状柱状交界处的细胞更深地位于粘膜下层。这些祖细胞可能具有同时产生基本鳞状和柱状细胞的潜力(如在BE中)，其分化的后代的命运由需要修复时产生的信号决定。根据物种的不同，祖先也可能存在差异。正常人的食道含有粘膜下腺和导管(ESMG/esMD)。传统的啮齿动物模型存在局限性，因为它们缺乏人类的食道腺和食道。因此，这些动物不足以模拟粘膜下祖细胞在BE和EAC启动中的潜在作用。在这里，我建议建立一个小动物模型(豚鼠)，以进一步了解粘膜下祖细胞在食道损伤和修复中的作用，以及基于大型动物(猪)的ESMG/esMD分离和培养系统。这个项目将作为我研究BE和EAC发展中的这些细胞的长期目标的一个培训工具和平台。为了实现我的长期目标，提高对高危人类食道疾病的早期发现，并影响与食管腺癌(EAC)相关的死亡率，我寻求进一步的职业发展，以获得上皮生物学、胃肠道干细胞生物学以及食道损伤和修复的动物模型方面的技能。杜克大学是一家久负盛名的研究机构，明确承诺支持初级教师的发展。我已经得到了独立的实验室空间和75%的保护研究时间。我很幸运，我有一个非常强大的指导团队和研究咨询委员会，帮助我在未来几年里过渡到一名独立的调查员，在基础科学技术方面拥有强大的技能，这些技能将通过拟议的工作得到发展。该项目将由胃肠道损伤和修复方面的细胞生物学和分子通路专家安娜·梅·迪尔博士指导，并由肠道干细胞生物学专家苏珊·亨宁博士共同指导。食道生物学、食道疾病动物模型和上皮修复方面的专家将提供额外的支持和技能培训。