Mechanisms of Pulmonary Fibrosis in Hermansky-Pudlak Syndrome

Hermansky-Pudlak 综合征肺纤维化的机制

• 批准号: 10165784
• 负责人: Lisa R. Young
• 金额: $ 44万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10165784
• 关键词: Adaptor Signaling Protein; Adult; Affect; Aging; Binding; Biogenesis; Blood Platelets; CCL2 gene; CRISPR/Cas technology; Cell Adhesion Molecules; Cell Culture Techniques; Cell membrane; Cell physiology; Cells; Coculture Techniques; Complex; Data; Defect; Development; Disease; Distal; Early Endosome; Endosomes; Epithelial; Epithelial Cells; Family; Fibroblasts; Fibrosis; Functional disorder; Funding; Genes; Genetic; Goals; Hereditary Disease; Hermanski-Pudlak Syndrome; Human; Interstitial Lung Diseases; Intervention; Knowledge; Link; Lung; Lysosomes; Mediating; Mediator of activation protein; Modeling; Molecular; Mus; Mutation; Oculocutaneous Albinism; Organelles; PAR-1 Receptor; Pathogenesis; Pathway interactions; Pharmacology; Phenotype; Predisposition; Prevention strategy; Production; Proteins; Publishing; Pulmonary Fibrosis; Receptor Cell; Receptor Signaling; Recycling; Research; Shortness of Breath; Signal Pathway; Signal Transduction; System; Testing; Therapeutic; Transforming Growth Factor beta; Transgenic Organisms; Transmembrane Transport; alveolar epithelium; base; cell injury; gene product; human disease; insight; macrophage; mouse model; novel therapeutics; prevent; protein transport; proteostasis; receptor; respiratory; trafficking; young adult

Hermansky-Pudlak Syndrome (HPS) is a family of autosomal recessive disorders characterized by oculocutaneous albinism and highly penetrant pulmonary fibrosis. Despite knowledge of the underlying genetic defects, there are currently no therapeutic or preventative approaches for HPS pulmonary fibrosis. Our published data demonstrate that alveolar epithelial cells (AECs) are the primary drivers of fibrotic susceptibility in HPS; however, the underlying mechanisms by which AECs dysfunction results in fibrosis remain undefined and represent an important knowledge gap in the field of fibrosis research. Studies during the current funding period have enabled us to define key phenotypes of HPS AECs with connections to fibrotic susceptibility in HPS mice. Specifically, we showed excess production of MCP-1 and increased Nox4-mediated ROS production by AECs contributes to fibrosis. A major goal of this proposal is to define how these pro-fibrotic AEC phenotypes relate to the underlying molecular defect in HPS. In search of a mechanism that underlies the observed pro-fibrotic phenotype of AECs in HPS, we recently identified increased TGFβ pathway activation in unstimulated HPS AECs. Activated type I and type II TGFβ receptors are constitutively recycled into endosomes, and early endosomes have been recognized as a vital signaling organelle for TGFβ signaling. Based on our preliminary data, we propose to investigate how compromised endosomal trafficking resulting from the genetic defect in HPS2 (loss of AP-3) alters proteostasis and dysregulates TGFβ signaling and AEC function. Our hypothesis is that defective endosomal trafficking in HPS alters TGFβ receptor signaling, thereby resulting in persistent and increased Smad and Erk1/2 signaling. These altered signaling pathways result in increased expression of MCP-1, Nox4, and other mediators by AECs that create a pro-fibrotic microenvironment in the distal lung. To test this hypothesis, we propose the following specific aims using cell culture models and a disease relevant HPS mouse model that develops spontaneous and progressive fibrosis with aging: 1) to determine how loss of AP-3 results in increased TGFβ signaling and expression of pro-fibrotic mediators by AECs, 2) to determine how AECs promote fibroblast activation in HPS, and 3) to investigate mechanisms of pulmonary fibrosis in HPS that develops with aging. Defining the mechanisms of AEC dysfunction in HPS could provide new insights into pathogenesis of HPS and other forms of pulmonary fibrosis, thus facilitating development of new therapeutic and preventative strategies for this fatal disorder.

赫曼斯基-普德拉克综合征 (HPS) 是一类常染色体隐性遗传疾病，其特征为 尽管了解潜在的遗传因素，但仍存在眼皮肤白化病和高度渗透性肺纤维化。 由于 HPS 肺纤维化存在缺陷，目前尚无治疗或预防方法。 已发表的数据表明，肺泡上皮细胞（AEC）是纤维化易感性的主要驱动因素 然而，在 HPS 中，AEC 功能障碍导致纤维化的潜在机制仍不清楚 并代表了当前资助期间纤维化研究领域的重要知识差距。 时期使我们能够定义与纤维化易感性相关的 HPS AEC 的关键表型 具体来说，我们发现 MCP-1 产生过量，Nox4 介导的 ROS 增加。 AEC 的产生会导致纤维化，该提案的一个主要目标是确定这些促纤维化的机制。 AEC 表型与 HPS 的潜在分子缺陷相关 寻找潜在的机制。 根据观察到的 HPS 中 AEC 的促纤维化表型，我们最近发现 TGFβ 途径激活增加 在未刺激的 HPS AEC 中，激活的 I 型和 II 型 TGFβ 受体被组成性地循环到体内。 内体和早期内体已被认为是 TGFβ 信号传导的重要信号细胞器。 根据我们的初步数据，我们建议调查内体运输受损是如何导致的 HPS2 的遗传缺陷（AP-3 缺失）会改变蛋白质稳态并失调 TGFβ 信号传导和 AEC 我们的假设是 HPS 中的缺陷内体运输改变了 TGFβ 受体信号传导，从而改变了 TGFβ 受体信号。 导致 Smad 和 Erk1/2 信号传导持续增加。 AEC 增加 MCP-1、Nox4 和其他介质的表达，从而产生促纤维化 为了检验这一假设，我们提出了使用细胞的以下具体目标。 培养模型和疾病相关的 HPS 小鼠模型，可发生自发性和进行性纤维化 随着衰老：1) 确定 AP-3 的缺失如何导致 TGFβ 信号传导和促纤维化表达增加 AEC 介导的介质，2) 确定 AEC 如何促进 HPS 中的成纤维细胞活化，以及 3) 进行研究 随着衰老而发展的 HPS 肺纤维化的机制 定义 AEC 的机制。 HPS 的功能障碍可以为 HPS 和其他形式的肺纤维化的发病机制提供新的见解， 从而促进针对这种致命疾病开发新的治疗和预防策略。