Hormonal Control of Lung Development: PTHrP Biology

描述(申请人提供)：肺泡发育由 终末呼吸道液体扩张和细胞变形。这些小路和 在肺组织中传递这些机械信号的效应分子 人们对发展的理解还不够深入。我们的长期目标是确定 生理和分子基础的细胞和分子机制 组织拉伸(机械变形)对胎儿的病理生理影响 肺部发育。我们已经确定甲状旁腺激素相关蛋白 甲状旁腺素受体(PTHrP)是一种由肺II型(Til)细胞表达的拉伸诱导信号。 甲状旁腺素受体促进胎儿肺发育，部分是通过刺激分化。 间充质细胞分化为脂成纤维细胞(LIF)。反过来，成熟的LIF表达 刺激瓷砖的生长因子和造脂蛋白，包括瘦素 细胞表面活性物质磷脂合成。我们的初步研究表明 机械力在多个点上与上皮间充质相互作用 促进肺泡分化的成熟环。我们还确定了 PTHrP信号或其下游信号的中断或抑制 效应器，可干扰肺泡功能，并导致分化 LIF转化为肌成纤维细胞(MYF)，导致肺瘢痕形成。基于这些 发现，我们计划证明甲状旁腺素受体和“生理学”机械 变形相互作用促进肺间充质细胞分化 LiF途径。相反，我们假设PTHrP耗竭干扰将 导致肺泡功能障碍和间充质向MYF分化 表型。在本提案的目标1中，我们将定义 远端肺发育过程中PTHrP信号和机械力的变化 确定甲状旁腺素rP诱导分化的分子机制 间充质细胞转化为生命周期因子。在目标2中，我们将确定细胞内 介导PTHrP刺激的信号通路和旁分泌效应 LIF分化促进TIL细胞分化。了解这些 机制将增强对正常牙槽骨形成和对 并可能导致治疗婴儿慢性肺部疾病的新疗法。

DESCRIPTION (provided by applicant): Alveolar lung development is molded by fluid distension of terminal airways and cellular deformation. The pathways and effector molecules that transduce these mechanical signals during lung development are not well understood. Our long-term objective is to identify the cellular and molecular mechanisms that underlie the physiologic and pathophysiologic effects of tissue stretch (mechanical deformation) on fetal lung development. We have determined that parathyroid hormone-related protein (PTHrP) is a stretch-inducible signal expressed by lung type II (Til) cells. PTHrP promotes fetal lung development, in part, by stimulating differentiation of mesenchymal cells into lipofibroblasts (LIFs). In turn, mature LIFs express growth factors and lipogenic proteins, including leptin, which stimulate Til cell surfactant phospholipid synthesis. Our preliminary studies indicate that mechanical forces interact at several points with this epithelial-mesenchymal maturational loop to promote alveolar differentiation. We also have determined that disruption or inhibition of PTHrP signaling, or of its downstream effectors, can interfere with alveolar function and cause differentiation of LIFs into myofibroblasts (MYFs), resulting in lung scarring. Based on these findings, we plan to demonstrate that PTHrP and "physiologic" mechanical deformation interact to promote lung mesenchymal cell differentiation along the LIF pathway. Conversely, we hypothesize that PTHrP depletion interference will lead to alveolar dysfunction and mesenchymal differentiation to the MYF phenotype. In Aim 1 of this proposal, we will define the interactions between PTHrP signaling and mechanical forces during development of the distal lung and determine the molecular mechanisms underlying PTHrP-inducible differentiation of mesenchymal cells into LIFs. In Aim 2, we will determine intracellular signaling pathways and paracrine effectors that mediate how PTHrP-stimulated LIF differentiation promotes Til cytodifferentiation. Understanding these mechanisms will enhance knowledge of normal alveolization and response to injury, and may lead to novel treatments for chronic lung disease in infants.