Hormonal Control of Lung Development: PTHrP Biology

描述（由申请人提供）：肺泡发育是由终末气道的液体扩张和细胞变形塑造的。在肺发育过程中抑制这些机械信号的途径和效应分子还没有很好的理解。 我们的长期目标是确定旁分泌机制的生理和病理生理影响的组织拉伸（机械变形）对胎儿肺发育。甲状旁腺激素相关蛋白（PTHRP）是由肺II型（TII）细胞表达的牵张诱导信号，其部分地通过刺激间充质细胞分化成脂肪成纤维细胞（LIF）来促进胎儿肺发育。成熟LIF表达生长因子和脂肪生成蛋白，包括瘦素，其刺激TII细胞表面活性剂合成。我们还确定PTHrP/PKA信号传导的破坏或抑制导致LIF分化为肌成纤维细胞（MYF），导致肺分隔或瘢痕形成。基于这些发现，我们将确定如何使用这些相同的旁分泌相互作用来有效地诱导胚胎干细胞（ES）分化为TIIs，LIFs或MYFs。 在母案申请的目的1中，我们定义了在远端肺发育期间PTHrP信号传导和机械力之间的相互作用，并确定了间充质细胞向LIF分化的PTHrP诱导分化的分子机制。在补充中，我们将用PTHrP和/或cAMP激动剂处理ES以诱导TII和LIF之间的信号传导，并确定如何加速ES分化为TII或LIF。 相反，我们将通过用PTHrP拮抗剂处理ES细胞来诱导ES细胞的MYF分化。 在母案申请的目的2中，我们确定瘦素信号传导如何促进TII细胞分化。 因此，在补充剂中，我们将通过用PTHrP或cAMP激动剂处理ES细胞来诱导瘦素（LIF）和瘦素受体（TII）表达。了解这些机制将有助于了解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病。

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.