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.

Hermansky-Pudlak综合征（HPS）是一个常染色体隐性疾病的家族，其特征是 眼皮白化病和高度穿透性肺纤维化。尽管有基础遗传 缺陷，目前尚无HPS肺纤维化的治疗方法或预防方法。我们的 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 在HPS中；但是，AEC功能障碍导致纤维化的基本机制仍然不确定 并代表纤维化研究领域的重要知识差距。在当前资金期间的研究 时期使我们能够定义HPS AEC的关键表型，并在 HPS小鼠。具体而言，我们显示了MCP-1的过量产生，并增加了NOX4介导的ROS AEC的生产有助于纤维化。该提案的主要目标是定义这些促纤维化如何 AEC表型与HPS中的潜在分子缺损有关。寻找一种基础的机制 观察到的HPS中AEC的促纤维化表型，我们最近确定了TGFβ途径的增加 在未刺激的HPS AEC中。激活的I型和II型TGFβ受体被组成地回收到 内体和早期内体被认为是TGFβ信号传导的重要信号细胞器。 根据我们的初步数据，我们建议研究如何妥协内体贩运 HPS2（AP-3的丢失）中的遗传缺陷会改变蛋白质，并使TGFβ信号传导和AEC失调 功能。我们的假设是，HPS中有缺陷的内体运输会改变TGFβ受体信号，从而改变 导致持久性并增加了SMAD和ERK1/2信号。这些改变的信号通路导致 通过AEC提高了MCP-1，NOX4和其他介体的表达，从而产生促纤维化 圆盘肺中的微环境。为了检验这一假设，我们提出了以下特定目的 培养模型和疾病相关的HPS小鼠模型，该模型开发赞助商和进行性纤维化 随着衰老：1）确定AP-3的损失如何导致TGFβ信号的增加和促纤维化的表达 AEC的介体，2）确定AEC如何促进HPS中的成纤维细胞激活，以及3）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HP和其他形式的肺纤维化的发病机理提供新的见解， 因此为这种致命疾病开发了新的治疗和预防策略。