Hormonal Control of Lung Development: PTHrP Biology

描述（由申请人提供）：肺泡发育由 终末气道的液体扩张和细胞变形。道路和 在肺循环中抑制这些机械信号的效应分子 发展并没有得到很好的理解。我们的长远目标是找出 细胞和分子机制的基础上的生理和 组织拉伸（机械变形）对胎儿的病理生理影响 肺发育我们已经确定甲状旁腺相关蛋白 PTHrP（PTHrP）是由肺II型（TII）细胞表达的牵张诱导信号。 PTHrP部分通过刺激分化促进胎肺发育 将间充质细胞转化为脂肪成纤维细胞（LIF）。反过来，成熟的LIF表达 生长因子和脂肪生成蛋白，包括瘦素，其刺激Til 细胞表面活性剂磷脂合成。我们的初步研究表明， 机械力在几个点上与这种上皮-间质细胞相互作用， 成熟环，促进肺泡分化。我们还确定 破坏或抑制PTHrP信号传导，或其下游 效应器，可以干扰肺泡功能，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 研究结果，我们计划证明PTHrP和“生理”机械 变形相互作用，促进肺间充质细胞分化沿着 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分化为MYF 表型。在本提案的目标1中，我们将定义 PTHrP信号和机械力在远端肺发育过程中的作用， 确定PTHrP诱导分化的分子机制 转化为LIF。在目标2中，我们将确定细胞内 信号通路和旁分泌效应器介导PTHrP刺激 LIF分化促进Til细胞分化。了解这些 机制将增强对正常肺泡化和对 损伤，并可能导致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.