PULMONARY DEVELOPMENT-- MOLECULAR & CELLULAR ANALYSIS

肺部发育——分子

• 批准号: 6527088
• 负责人: Parviz Minoo Minoo
• 金额: $ 32.5万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-08-01 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6527088
• 关键词: biological signal transduction; bone morphogenetic proteins; cell differentiation; collagen; developmental genetics; extracellular matrix proteins; gene expression; gene targeting; genetic promoter element; genetic regulation; genetic regulatory element; genetically modified animals; histogenesis; immunocytochemistry; in situ hybridization; integrins; laboratory mouse; lung; oligonucleotides; protein protein interaction; protein structure function; reporter genes; respiratory epithelium; tissue /cell culture; transcription factor

It is not well established that Nkx2.1 is a critical regulator of lung morphogenesis and differentiation of pulmonary specialized epithelial cells. The precise role of NKX2.1 peptide appears to be related to Proximo-Distal lung morphogenesis. Recent data demonstrate that Nkx2.1 is upstream of a battery of morphoregulatory genes. In particular, the gene encoding the signaling molecule BMP4 is undetectable in Nkx2.1(-/-) lungs, as are the ECM protein Collagen type IV and the cellular receptors alpha1, alpha2, and alpha3 integrins. Abrogation of BMP4 signaling by transgenic means results in loss of distal lung structures implicating both Collagen and alpha-integrins in lung branching morphogenesis. The sum of the accumulated data from the last funding period of HL-56590 now provides the opportunity and the rationale to examine the possible functional integration amongst the three classes of transcription factors, signaling molecules and the ECM. In addition, precise spatio-temporal regulation of Nkx2.1 expression is critical to its function, but the in vivo mechanisms remain unknown. Three specific aims are proposed with the distinct goal of examining the overall hypothesis that developmentally regulated expression of Nkx2.1 directs proximo-distal lung morphogenesis through precise spatio-temporal activation of downstream target genes (e.g. Bmp4, collagen IV and alpha-integrins). Specific Aim 1 is to characterize the specificity of the Bmp4 pathway in lung morphogenesis. Specific Aim 2 is to determine the precise regulatory relationship among Nkx2.1, Bmp4, and the ECM (collagen IV and alpha-integrins). Specific Aim 3 is to determine the regulation of Nkx2.1 gene expression. By the completion of the described studies the authors intend to gain a better understanding of the how morphogenesis and cellular differentiation along the proximo-distal axis of the lung is regulated.

Nkx2.1是肺形态发生的关键调节因子， 肺特化上皮细胞的分化。NKX2.1的确切作用 肽似乎与近端-远端肺形态发生有关。最近的数据 证明Nkx2.1是一组形态调控基因的上游。在 特别地，编码信号传导分子BMP 4的基因在哺乳动物中是检测不到的。 Nkx2.1（-/-）肺，如ECM蛋白IV型胶原和细胞外基质蛋白。 受体α 1、α 2和α 3整联蛋白。BMP 4信号传导的消除 转基因方法导致远端肺结构的丧失， 肺分支形态发生中的胶原和α-整合素。之和 从HL-56590的最后一个资助期积累的数据现在提供了机会， 以及研究三者之间可能的功能整合的理由 转录因子、信号分子和ECM的类别。此外，本发明还提供了一种方法， Nkx2.1表达的精确时空调控对于其表达的调控至关重要。 功能，但在体内机制仍然未知。三个具体目标是 提出的明确目标是检验总体假设， Nkx2.1的发育调节表达指导近端-远端肺 通过精确时空激活下游靶点的形态发生 基因（例如Bmp 4、胶原IV和α-整联蛋白）。 具体目标1是 表征Bmp 4途径在肺形态发生中的特异性。 具体目标2是确定以下各项之间的精确调节关系： Nkx2.1、Bmp 4和ECM（胶原IV和α-整联蛋白）。 具体目标3是 以确定Nkx2.1基因表达的调控。 在完成 描述的研究，作者打算更好地了解如何 形态发生和细胞分化沿着近远轴的 肺是有规律的。