Hormonal Control of Lung Development: PTHrP Biology

描述(申请人提供)：肺泡发育是由末端呼吸道的液体膨胀和细胞变形形成的。在肺发育过程中传递这些机械信号的途径和效应分子还不是很清楚。我们的长期目标是确定组织拉伸(机械变形)对胎肺发育的生理和病理生理学影响的旁分泌机制。甲状旁腺激素相关蛋白(PTHrP)是一种可拉伸诱导的信号，由肺II型(TII)细胞表达，部分通过刺激间充质细胞向成纤维细胞(LIF)分化促进胎儿肺发育。成熟的LIF表达生长因子和造脂蛋白，包括瘦素，它们刺激TII细胞表面活性物质的合成。我们还确定，PTHrP/PKA信号通路的中断或抑制会导致LIF分化为肌成纤维细胞(MYF)，从而导致肺间隔或瘢痕形成。基于这些发现，我们将确定如何利用这些旁分泌相互作用有效地诱导胚胎干细胞分化为TII、LIF或MYF。目的1在亲代应用中，我们正在定义PTHrP信号和远端肺发育过程中的机械力之间的相互作用，并确定PTHrP诱导间充质细胞分化为LIF的分子机制。在补充中，我们将用PTHrP和/或cAMP激动剂治疗ES，以诱导TII和LIF之间的信号转导，并确定如何加速ES向TII或LIF的分化。相反，我们将通过PTHrP拮抗剂诱导ES细胞分化为MYF。在父应用程序的目标2中，我们正在确定瘦素信号如何促进TII细胞分化。因此，在补充中，我们将通过PTHrP或cAMP激动剂处理ES细胞来诱导瘦素(LIF)和瘦素受体(TII)的表达。了解这些机制将增进关于干细胞如何在肺损伤/修复中发挥作用，以及如何有效地用于治疗婴儿肺损伤和慢性肺部疾病的知识。

DESCRIPTION (provided by applicant): Alveolar lung development is molded by fluid distension of terminal airways and cellular deformation. The pathway and effector molecules that transduce these mechanical signals during lung development are not well understood. Our long-term objective is to identify the paracrine mechanisms that underlie the physiologic and pathophysiologic effects of tissue stretch (mechanical deformation) on fetal lung development. Parathyroid Hormone-related Protein (PTHRP) is a stretch-inducible signal expressed by lung type II (TII) cells that promotes fetal lung development, in part, by stimulating differentiation of mesenchymal cells into lipofibroblasts (LIFs). The Mature LIFs express growth factors and lipogenic proteins, including leptin, which stimulate TII cell surfactant synthesis. We also have determined that disruption or inhibition of PTHrP/PKA signaling causes differentiation of LIFs into myofibroblast, (MYFs), leading to lung septation or scarring. Based on these findings, we will determine how these same paracrine interactions may be used to effectively induce embryonic stem (ES) cell differentiation into TIIs, LIFs or MYFs. Aim 1 of the parent application we are defining the interactions between PTHrP signaling and mechanical force during development of the distal lung, and determining the molecular mechanisms underlying PTHrP-inducible differentiation of mesenchymal cells into LIFs. In the supplement, we will treat ES with PTHrP and/or cAMP agonists to induce signaling between TIIs and LIFs, and determine how ES differentiation into TIIs or LIFs can be accelerated. Conversely, we will induce MYF differentiation of ES cells by treating them with a PTHrP antagonist. In Aim 2 of the parent application, we are determining how leptin signaling promotes TII cytodifferentiation. Therefore, in the supplement we will induce leptin (LIF) and leptin receptor (TII) expression by treating ES cell with PTHrP or cAMP agonists. Understanding these mechanisms will enhance knowledge as to how stem cell function in lung injury/repair, and how they may be used effectively to treat lung injury and chronic lung disease in infants.