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Role of Fgfr2IIIb in epithelial mesenchymal signaling in intestinal development

Fgfr2IIIb 在肠道发育中上皮间质信号传导中的作用

基本信息

批准号：
8637990
负责人：
Peter F Nichol
金额：
$ 16.16万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8637990
关键词：
Address Area Award Basic Science Biological Markers Cell Death Cells Clinical Complement Country Data Defect Development Developmental Biology Ensure Environment Epithelial Epithelial Cells Epithelium Erinaceidae Ethics Etiology Event Faculty Failure Fibroblast Growth Factor Foundations Funding Gene Expression Genetic Models Goals Growth Growth and Development function Human Individual Institution Intervention Intestinal Atresia Intestinal Obstruction Intestines Iron Large Intestine Lead Leadership Mammalian Genetics Mentors Mentorship Mesenchymal Mesenchyme Mesoderm Molecular Mus Mutagenesis Mutation Neonatal Obstruction Operative Surgical Procedures Patients Positioning Attribute Radial Research Research Personnel Resolution Resources Role Scientist Short Bowel Syndrome Signal Transduction Small Intestines Solutions Surgeon Testing Time Tissues Training Tube United States Universities Wages Wisconsin career career development critical developmental period directed attention insight interest meetings mutant novel postnatal programs receptor regenerative therapy smoothened signaling pathway therapy development

项目摘要

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.

候选人：我的职业目标是成为短肠综合征患者肠道发育研究和翻译疗法开发的领先者。为了实现这一目标，我将在发育生物学、上皮-间充质信号以及研究过程中的伦理学方面接受基础科学方面的强化培训。这将包括正式的课程作业，在实验室会议上的一对一指导报告，系和大学范围内的研讨会和全国会议。我将带领一个新成立的研究团队研究肠道闭锁，为了解肠道纵向生长的机制奠定科学基础。我将为短肠综合征患者开始一项全面的临床计划，以便建立一个临床部分，以补充我的科学兴趣。我将不迟于获奖期的第三年提交R01申请。最后，我将寻求国家组织的领导职位，以加强这一领域的合作努力，并直接关注和提供资源，为这一问题制定治疗方法和解决办法。所有这些步骤都将有助于我成功地过渡到独立。环境：威斯康星大学是美国一流的研究机构之一，校园里有800多名生物学家。在联邦政府资助和外科科学家的职业发展方面，外科系享有全国最高声誉之一。该部调动了大量资源，对尼科尔博士的职业发展作出了坚定的承诺，包括保证3年的工资、启动资金(300 000美元)和每年9个月的受保护时间。此外，尼科尔博士将得到两位顶尖的发育生物学家和该校最成功的导师(布什曼博士和法伦博士)以及其他杰出教职员工的指导。这些组成部分将为他提供一个最佳的研究环境，确保他成功地过渡到独立。研究：本研究的长期目标是了解肠闭锁的病因，并为再生治疗建立科学基础，以解决通常伴随闭锁的短肠综合征的特征。肠闭锁是由肠道发育过程中的节段性缺陷引起的。这会导致肠道连续性和肠梗阻的丧失。成纤维细胞生长因子信号是肠道生长发育的重要调节因子。我们的初步研究表明，结肠上皮中Fgfr2IIIb的条件突变在小鼠身上产生了相当于人类缺陷的节段性闭锁。在闭锁形成之前，上皮分化失败，随后间充质的径向和纵向生长中断。我们已经确定Foxf1表达的缺失是闭锁节段内这一事件的特异性生物标记物。Foxf1是Hedgehog(HH)信号通路的关键间充质组织者和靶标。我们假设，在关键的发育时期，当这些信号引导间充质的径向和纵向生长时，上皮-间充质信号的节段性中断导致了畸形的发生。具体地说，我们假设上皮细胞Hedgehog信号是这种间充质生长的关键调节因子，持续的HH信号依赖于通过激活Fgfr2IIIb受体实现的上皮细胞自主分化。因此，上皮Fgfr2IIIb表达的缺失被预测会导致细胞自主分化失败、HH信号中断、间充质生长失败和随后的闭锁形成。我们将在以下目标中检验这些预测：具体目的1：验证Fgfr2IIIb突变破坏上皮细胞分化导致中胚层生长、增殖和Foxf1基因表达改变的假说。特定目的2：验证Fgfr2IIIb条件突变体中上皮细胞分化的丧失是一种细胞自主事件的假设，该事件完全是由于Fgfr2IIIb的表达丧失所致。具体目标3：验证Fgfr2IIIb条件突变体中间充质生长减少是上皮Hedgehog信号丢失的直接结果的假设。我们将在小鼠中采用条件突变策略来描述上皮和间充质之间的特定相互作用，以及上皮细胞中Fgfr2IIIb受体在正常肠道发育和闭锁形成中的功能。这种方法将提供干净、高分辨率的数据，并允许我们在哺乳动物遗传模型中直接测试我们的假设，该模型紧密地概括了人类的发育。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Haploinsufficiency of retinaldehyde dehydrogenase 2 decreases the severity and incidence of duodenal atresia in the fibroblast growth factor receptor 2IIIb-/- mouse model.

DOI：
10.1016/j.surg.2012.07.022
发表时间：
2012-10
期刊：
SURGERY
影响因子：
3.8
作者：
Reeder, Amy L.;Botham, Robert A.;Zaremba, Krzysztof M.;Nichol, Peter F.
通讯作者：
Nichol, Peter F.

A more efficient method to generate null mutants using Hprt-Cre with floxed alleles.

DOI：
10.1016/j.jpedsurg.2011.01.023
发表时间：
2011-09
期刊：
JOURNAL OF PEDIATRIC SURGERY
影响因子：
2.4
作者：
Nichol, Peter F.;Botham, Robert;Saijoh, Yukio;Reeder, Amy L.;Zaremba, Krzyztoff M.
通讯作者：
Zaremba, Krzyztoff M.

Exogenous Sonic hedgehog protein does not rescue cultured intestine from atresia formation.

DOI：
10.1016/j.jss.2013.11.1114
发表时间：
2014-03
期刊：
JOURNAL OF SURGICAL RESEARCH
影响因子：
2.2
作者：
Reeder, Amy L.;Zaremba, Krzysztof M.;Liebl, Rebeca M.;Kowalkowski, Anna;Nichol, Peter F.
通讯作者：
Nichol, Peter F.

Formation of duodenal atresias in fibroblast growth factor receptor 2IIIb-/- mouse embryos occurs in the absence of an endodermal plug.