Mechanisms of intestine development

描述(由申请者提供)：这份由NIDDK指导的研究科学家发展奖申请描述了一项为期5年的培训计划，旨在让我获得更多的技能和知识，以便我能够过渡到一名独立的研究科学家。在进行拟议的研究时，通过遵循我的职业发展计划，我将增加我的科学技能，并获得肠道发育生物学方面的专业知识。利用这些新获得的肠道发育专业知识，我将建立一个科学利基，这将使我有别于我的导师，并为一个强大的、外部资助的研究计划铺平道路。在这项申请中提出的研究将专注于了解胚胎肠道中的干细胞/祖细胞是如何使用传统的小鼠遗传学和我们开发的一种新的体外系统来指定和调控的，该系统允许我们在培养中从人类胚胎和诱导的多能干细胞中产生人类肠道组织。在培养中产生人类肠道组织将允许对人类肠道发育、体内平衡和疾病进行前所未有的研究。其具体目的是测试一种模型，在该模型中，Sox9调节早期肠道祖细胞，因为它们仅限于发育中的肠道的增殖绒毛间区。具体目标1将利用谱系标记和细胞示踪实验研究人和小鼠肠道干细胞的胚胎发育。特定目的2将确定Sox9在调节人和小鼠肠道绒毛间区胚胎发育中的作用。具体目标3将研究Wnt信号在发育过程中绒毛间祖细胞区的建立中的抑制作用。总而言之，这里提出的研究符合Trans-NIH报告《消化系统疾病研究中的机遇和挑战：国家消化系统疾病委员会的建议》(2009)，该报告指出：“揭示控制出生前和新生儿生活中消化道发育和分化的机制，可以为治疗消化系统癌症和其他疾病的再生疗法带来新的见解，并为疾病的发病机制提供新的见解。”这个有指导的研究科学家发展奖的目标是发展专业知识，使我能够运行一个独立的、受资助的研究项目，为改善人类健康和疾病做出贡献。

DESCRIPTION (provided by applicant): This NIDDK Mentored Research Scientist Development Award application describes a 5-year training plan designed to allow me to gain additional skill and knowledge so that I can transition into an independent research scientist. In carrying out the proposed research, and by following my career development plan I will add to my scientific repertoire and acquire expertise in intestinal developmental biology. Using this newly acquired expertise in intestine development, I will establish a scientific niche that will set me apart from my mentors and pave the way to a robust, extramurally funded research program. The research proposed in this application will focus on understanding how the stem/progenitor cells in the embryonic intestine are specified and regulated using both traditional mouse genetics, and a novel in vitro system we have developed that allows us to generate human intestinal tissue in culture from human embryonic and induced pluripotent stem cells. Generation of human intestinal tissue in culture will allow for unprecedented studies of human intestinal development, homeostasis and disease. The specific aims are designed to test a model where Sox9 regulates early intestinal progenitor cells as they are restricted to the proliferative intervillus region of the developing intestine. Specific Aim 1 will investigate the embryonic development of human and mouse intestinal stem cells using lineage labeling and cell tracing experiments. Specific Aim 2 will determine the role of Sox9 in regulating embryonic development of the intervillus region in human and mouse intestine. Specific Aim 3 will investigate a suppressive role for Wnt signaling in establishment of the intervillus progenitor zone during development. Collectively, the research proposed here is in line with the Trans-NIH Report "Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases" (2009) which states: "Uncovering the mechanisms that control development and differentiation of the digestive tract before birth and in neonatal life could generate new insights for regenerative therapies to treat digestive cancers and other diseases, as well as provide new insights into disease pathogenesis." The goal of this Mentored Research Scientist Development Award is to develop the expertise that will allow me to run an independent, funded research program that will contribute to improving human health and disease.