Role of Fgfr2IIIb in epithelial mesenchymal signaling in intestinal development

候选人：我的职业目标是成为肠道发育研究和短肠综合征患者转化疗法开发的领导者。为了实现这一目标，我将接受发育生物学、上皮-间充质信号传导以及研究伦理等基础科学方面的强化训练。这将包括正式的课程，在实验室会议上进行一对一的指导演讲，系里和大学范围内的研讨会以及全国会议。我将带领一个新生的研究团队进行肠道闭锁的研究，为理解纵向肠道生长机制奠定科学基础。我将开始一项针对短肠综合征患者的综合临床计划，以建立一个临床成分，以补充我的科学兴趣。我将不迟于奖励期的第三年提交R01申请。最后，我将在国家组织中寻求领导职位，以加强这一领域的合作努力，并直接关注和资源，以开发针对这一问题的治疗和解决方案。所有这些步骤将有助于我成功过渡到独立。

Candidate: My career goals are to become a leader in the study of intestinal development and development of translational therapies for patients with short gut syndrome. To achieve this I will undergo intensive training in the basic sciences in developmental biology, epithelial-mesenchymal signaling as well as ethics in the conduct of research. This will include formal coursework, one-on-one mentorship presentations at lab meetings, department and University-wide seminars and national meetings. I will lead a nascent team of investigators in the study of intestinal atresia to develop a scientific foundation for understanding the mechanisms of longitudinal intestinal growth. I will begin a comprehensive clinical program for patients with short gut syndrome in order to establish a clinical component that will complement my scientific interests. I will submit an R01 application no later than year 3 of the award period. Finally, I will seek leadership positions in national organizations in order to enhance collaborative efforts in this area as well as direct attention and resources towards developing therapies and solutions for this problem. All of these steps will facilitate my successful transition to independence. Environment: The University of Wisconsin is one of the premier research institutions in the United States with over 800 biologists on campus. The Department of Surgery enjoys a reputation as one of the top in the country in terms of federal funding and career development of surgeon-scientists. The Department has mobilized its significant resources in making an iron clad commitment to Dr. Nichol's career development including guarantees for 3 years of salary, start-up funds ($300,000) and 9 months of protected time per year. In addition, Dr. Nichol will be mentored by two of the premier developmental biologists and most successful mentors on this campus (Drs. Bushman and Fallon) as well as other outstanding faculty. These components will provide him with an optimal research environment that will ensure that his transition to independence is successful. Research: The long term goal of this research is to understand the etiology of intestinal atresias and to establish the scientific foundation for regenerative therapies to address the features of short gut syndrome that often accompany atresia. Intestinal atresia arises from a segmental defect in intestinal development. This results in a loss of intestinal continuity and obstruction. FGF signaling is a critical regulator of intestinal growth and development. Our preliminary studies indicate that conditional mutation of Fgfr2IIIb in the colonic epithelium produces a segmental atresia in mice equivalent to the human defect. The formation of atresia is preceded by a failure in epithelial differentiation and a subsequent disruption in radial and longitudinal growth of the mesenchyme. We have identified loss of Foxf1 expression as a specific biomarker for this event within the segment that will undergo atresia. Foxf1 is a critical mesenchymal organizer and target of the hedgehog (Hh) signaling pathway. We hypothesize that atresias arise from a segmental disruption in epithelial-mesenchymal signaling during a critical developmental period when these signals direct both radial and longitudinal growth of the mesenchyme. Specifically, we postulate that epithelial hedgehog signaling is a critical regulator of this mesenchymal growth and that sustained Hh signaling is dependent upon cell autonomous differentiation of the epithelium by activation of the Fgfr2IIIb receptor. Accordingly, loss of epithelial Fgfr2IIIb expression is predicted to result in a failure in cell autonomous differentiation, disruption of Hh signaling, failed mesenchymal growth and subsequent atresia formation. We will test these predictions in following aims: Specific Aim 1: Test the hypothesis that Fgfr2IIIb mutation disrupts epithelial differentiation leading to alterations in growth, proliferation and Foxf1 gene expression in the mesoderm. Specific Aim 2: Test the hypothesis that loss of epithelial differentiation in the Fgfr2IIIb conditional mutants is a cell autonomous event due exclusively to a loss of Fgfr2IIIb expression. Specific Aim 3: Test the hypothesis that the reduced mesenchymal growth in the Fgfr2IIIb conditional mutant is a direct result of loss of epithelial Hedgehog signaling. We will employ a conditional mutagenesis strategy in mice to delineate specific interactions between epithelium and mesenchyme and the function of the Fgfr2IIIb receptor in epithelial cells in normal intestinal development and atresia formation. This approach will provide clean, high resolution data and permit us to directly test our hypotheses in a mammalian genetic model that closely recapitulates development in the human.