Mechanism of Lung Development and Injury

描述（由申请人提供）：转化生长因子是分泌的多肽，具有生理和病理功能。两种受体酪氨酸激酶T <$RI和T <$RII介导TGF-β信号对细胞表面的影响。在肺发育和疾病中，两种受体之间的功能特异性和差异，在配体结合之后还没有被严格地和机械地解决。我们已经发现，TGF-β通过T <$RII信号传导在肺的形态发生和损伤中起着关键作用。在间充质中，我们发现T <$RII是通过Shh进行正常上皮-间充质通讯所需的。在上皮细胞中，通过T <$RII的信号传导调节肺泡形成，并且在博莱霉素诱导的肺损伤中是必需的。基于这些概念，我们提出了以下假设：假设：正常的肺发育和博莱霉素诱导的肺损伤依赖于TGF-β信号通过T <$RII。后一种假设得到了现有数据的支持，并且其一些预测可以通过以下四个具体目标直接检验：具体目标1。确定Shh和TGF-β信号通路之间的串扰机制。具体目标2。确定TGF-β通路中介导与Shh通路交叉的组分。具体目标3。确定上皮T <$RII在博莱霉素诱导的小鼠肺纤维化模型发病机制中的潜在作用。健康相关性：TGF-β与许多肺部疾病有关，包括肺纤维化和支气管肺发育不良。据我们所知，本申请中提出的研究是第一个解决细胞特异性（上皮细胞对间充质细胞）通过T？RII的信号传导对肺损伤发病机制的贡献的研究。公共卫生相关性：该项目将使用特定的遗传工具来研究TGF-β在肺发育过程中的作用以及新生儿和成人慢性疾病的发病机制。

DESCRIPTION (provided by applicant): Transforming growth factors-¿ are secreted polypeptides that render both physiological and pathological functions. Two receptor tyrosine kinases, T¿RI and T¿RII mediate the impact of TGF-¿ signaling on the cell surface. Functional specificity and differences between the two receptors, subsequent to ligand binding have not been rigorously and mechanistically addressed in lung development and disease. We have found that TGF-¿ signaling through the T¿RII plays a critical role in both morphogenesis and injury in the lung. In the mesenchyme, we found T¿RII to be required for normal epithelial-mesenchymal communication through Shh. In the epithelium, signaling through T¿RII regulates alveolar formation, and is required in Bleomycin-induced lung injury. Based on these concepts, we have formulated the following hypothesis: HYPOTHESIS: Normal lung development and Bleomycin-induced lung injury are dependent on TGF-¿ signaling through T¿RII. The latter hypothesis is supported by the available data and some of its predictions are directly testable by the following four Specific Aims: Specific aim 1. To Determine the Mechanism of Cross-Talk Between Shh &TGF-¿ Signaling Pathways. Specific aim 2. To Identify Components of the TGF-¿ Pathway That Mediate the Cross-Talk With the Shh Pathway. Specific aim 3. To Determine the Potential Role of Epithelial T¿RII in Pathogenesis of Bleomycin-Induced Murine Model of Pulmonary Fibrosis. Health Relevance: TGF-¿ is implicated in many lung diseases including Pulmonary Fibrosis and Bronchopulmonary Dysplasia. To our knowledge, the studies proposed in this application are the first to address, cell-specifically (epithelial versus mesenchymal) the contributions of signaling through T¿RII to pathogenesis of lung injury. PUBLIC HEALTH RELEVANCE: This project will use specific genetic tools to study the role of TGF-¿ during lung development and in pathogenesis of neonatal and adult chronic diseases.