Submucosal esophageal structures as a progenitor niche for esophageal repair

描述（由申请人提供）：在我的培训到目前为止，我已经成功地完成了几个临床和成果研究项目，导致出版物。然而，在我担任杜克大学内科住院总医师的那一年里，意想不到的事情开始发生了：我对基础研究问题越来越感兴趣。因为我们似乎无法积极影响食管癌的发展速度，我对胃肠道癌前病变背后的分子事件越来越好奇。我开始考虑如何更好地了解基本的食管生物学可能转化为急需的进步，在病人筛选，监测和风险分层。这种对更深入的生物学理解的渴望推动了拟议项目和指导团队的形成。食管癌的五年生存率低于17%，食管腺癌（EAC）现在占食管癌病例的50%以上。目前的筛查工作未能影响死亡率。为了提高生存率，需要新的预防和早期发现战略。食管鳞状上皮基底层和鳞状-柱状交界处的鳞状祖细胞已被广泛研究。在人类中，高风险BE和EAC的祖细胞可能与基底鳞状上皮祖细胞不同（可能分化程度较低），并且这种人食管祖细胞可能位于粘膜下层比小鼠鳞状-柱状连接处发现的细胞更深的地方。这种祖细胞可能有潜力产生基底鳞状细胞和柱状细胞（如BE），其分化后代的命运由需要修复时产生的信号决定。基于物种的祖先也可能存在差异。正常人食管含有粘膜下腺体和导管（ESMG/ESMD）。传统的啮齿类动物模型是有限的，因为它们缺乏在人类中发现的食管腺和导管。因此，这些动物不足以模拟粘膜下祖细胞在BE和EAC起始中的潜在作用。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管损伤和修复中的作用，以及一个大动物（猪）为基础的系统ESMG/ESMD的分离和培养。这个项目将作为一个培训工具，以及我的长期目标，研究这些细胞在BE和EAC的发展平台。为了实现我的长期目标，以提高早期发现高风险的人类食管疾病和影响与食管腺癌（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和食管损伤和修复的动物模型的技能。杜克是一个完善的研究机构，有一个明确的承诺，以支持初级教师的发展。我已经获得了独立的实验室空间和75%的研究时间。我很幸运，有一个非常强大的指导团队和研究咨询委员会，以帮助促进我在未来几年的过渡，成为一个独立的调查员，在基础科学技术，将通过拟议的工作开发强大的技能。该项目将由安娜梅迪尔博士指导，她是胃肠道损伤和修复的细胞生物学和分子通路专家，并将由肠道干细胞生物学专家苏珊亨宁博士共同指导。食管生物学、食管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。

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.