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（由申请人提供）：到目前为止，在我的培训中，我已经成功完成了几个临床和成果研究项目，从而导致出版物。然而，在我担任杜克大学内科医学首席居民的一年中，意想不到的开始发生：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道癌发展的速度，所以我对胃肠道疾病前疾病背后的分子事件的好奇心越来越大。我开始考虑如何更好地理解基本的食管生物学可能会转化为患者筛查，监视和风险分解的急需进步。今年对更深入的生物学理解的向往促进了拟议项目和指导团队的成立。食管癌的五年生存率不到17％，而食管腺癌（EAC）现在占食管癌病例的50％以上。当前的筛查工作未能影响死亡率。为了提高生存，需要新的预防和早期检测策略。已经广泛研究了食管鳞状上皮和鳞状柱交界处的基底层中的鳞状祖细胞。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（也许差异化），并且该人类食管祖细胞可能与粘膜中的细胞更深，在粘液群中发现的细胞更深。这种祖细胞可能有可能引起基底鳞状和柱状细胞（如BE），其分化后代的命运是在需要修复时产生的信号确定的。基于物种的祖细胞也可能存在差异。正常的人类食管含有粘膜粘膜和管道（ESMG/ESMD）。传统的啮齿动物模型受到限制，因为它们缺乏人类中发现的食道腺和管道。因此，这些动物不足以建模粘膜下祖细胞在启动BE和EAC中的潜在作用。在这里，我建议开发一种小型动物模型（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，以及基于ESMG/ESMD的大动物（PIG）系统。该项目将用作训练工具，也是我在BE和EAC开发中研究这些细胞的长期目标的平台。为了实现我的长期目标，以改善高危人类食管疾病的早期检测以及与食管腺癌相关的影响死亡率（EAC），我寻求进一步的职业发展，以便获得上皮生物学，胃肠道干细胞生物学以及食管损伤和维修动物模型的技能。杜克大学是一家成熟的研究机构，对支持初级教师发展的明确承诺。我已经提供了独立的实验室空间，并保护了75％的研究时间。我很幸运能够建立一个非常强大的指导团队和研究咨询委员会，以帮助我在未来几年中促进我的过渡，成为一名独立研究者，具有强大的基础科学技术技能，这将通过拟议的工作开发。该项目将由胃肠道损伤和修复的细胞生物学和分子途径专家Anna Mae Diehl博士进行指导，并由肠道干细胞生物学专家Susan Henning博士共同管理。食管生物学，食管疾病的动物模型和上皮修复专家将提供其他支持和技能培训。