Cell: Cell Interactions During Late Intestinal Development

细胞：肠道发育后期的细胞相互作用

• 批准号: 6921710
• 负责人: DEBORAH L. GUMUCIO
• 金额: $ 34.76万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6921710
• 关键词: bioinformatics; biological signal transduction; cell cell interaction; cell proliferation; cellular polarity; chromatin immunoprecipitation; computer program /software; fibroblasts; gastrointestinal epithelium; gastrointestinal system; gene induction /repression; genetically modified animals; growth /development; intestinal villi; laboratory mouse; microarray technology

DESCRIPTION (provided by applicant): The small intestinal epithelium is organized into flask-like glands (crypts) that contain intestinal stem cells and finger-like projections (villi) covered by differentiated cells. A constant process of cell division, differentiation and migration is established along a polarized crypt to villus axis. Establishment and maintenance of this vertical axis requires cell:cell crosstalk between the epithelium and the underlying mesenchyme and is critical to proper homeostasis of the intestine. Analysis of a newly established mouse model in which hedgehog (Hh) signals are blocked (Hhip transgenic mice) reveals that establishment of the crypt/villus axis requires this signaling pathway. Hh signals emanate from the epithelium and are received by the mesenchyme. Shh and Ihh participate in this signal; these two signaling proteins have both overlapping and separate roles. Loss of the combined Hh signal permits the formation of ectopic pre-crypt structures on villus tips, thus disrupting the normal organization of the crypt/villus axis. The epithelial phenotype of Hhip mice reflects alterations in cell:cell crosstalk between the epithelial cells and an expanded population of subepithelial myofibroblasts. The proposal tests the following Hypothesis: A combined Ihh and Shh signal from the epithelium is received by subepithelial myofibroblasts and acts indirectly to limit and organize the Wnt responsive epithelial pre-crypt compartment. In Aim 1, the sequence of molecular and morphological events that accompany crypt/villus axis polarization during late intestinal development will be compared in wild type, Shh -/-, Ihh -/- and Hhip mice. In Aim 2, the targets of Hh signaling in the mesenchymal compartment will be identified. Separate and common targets of Shh and Ihh will be sought; the possibility that Hh induces different genes at different concentrations will be tested. Finally, Aim 3 explores how Hh proteins function to organize the crypt/villus axis (i.e., by polarization via a morphogen gradient or by anchoring of the pre-crypt region) and tests specific candidate genes for their role in patterning this axis. The work will provide new insights into cell:cell signaling pathways crucial for intestinal development.

描述（由申请人提供）：小肠上皮被组织成类似烧瓶的腺体（隐窝），其中包含肠道干细胞和手指样突起（Villi），被分化细胞覆盖。沿极化的隐窝建立了细胞分裂，分化和迁移的恒定过程。该垂直轴的建立和维护需要细胞：上皮和下面间质之间的细胞串扰，对于肠道的适当稳态至关重要。对新建立的小鼠模型的分析，其中刺猬（HH）信号被阻断（HHIP转基因小鼠）表明，建立隐窝/绒毛轴需要此信号传导途径。 HH信号从上皮散发出来，并由间充质接收。 SHH和IHH参与了这个信号；这两个信号蛋白既具有重叠和单独的角色。 HH联合信号的丢失允许在绒毛尖端形成异位前结构结构，从而破坏了隐窝/绒毛轴的正常组织。 HHIP小鼠的上皮表型反映了细胞的改变：上皮细胞之间的细胞串扰和上皮下肌纤维细胞的扩大群体。该提案检验以下假设：上皮下肌纤维细胞接收到上皮的IHH和SHH信号，并间接起作用以限制和组织Wnt响应性响应性响应性上皮上皮前室。在AIM 1中，将在野生型，SHH - / - ，IHH - / - 和HHIP小鼠中比较伴随着肠发育期间隐窝/绒毛轴极化的分子和形态事件的序列。在AIM 2中，将确定间充质室中HH信号的靶标。将寻求SHH和IHH的单独和共同目标； HH在不同浓度下诱导不同基因的可能性将被测试。最后，AIM 3探讨了HH蛋白如何组织隐窝/绒毛轴（即，通过通过形态学梯度或通过锚定固定前区域的偏振化或通过锚固区域的锚定）来测试特定候选基因在构图此轴上的作用。这项工作将为细胞提供新的见解：细胞信号传导途径对于肠道发育至关重要。