The role of the epithelial-derived chemokine, CXCL12, in Idiopathic Pulmonary Fibrosis

上皮源性趋化因子 CXCL12 在特发性肺纤维化中的作用

• 批准号: 10616468
• 负责人: Daniel Sullivan
• 金额: $ 0.65万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-16 至 2022-05-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10616468
• 关键词: Acute; Adopted; Adult; Affect; Age; Aging; Animal Model; Animals; Autocrine Communication; Biological Models; Bleomycin; Blood; CXCL12 gene; CXCR4 Receptors; Cell Aging; Cell Line; Cell model; Cells; Cellular biology; Characteristics; Chromosomes; Cicatrix; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; DNA; Data; Development; Diagnosis; Disease; Dominant-Negative Mutation; Elements; Environment; Epithelial; Epithelial Cell Proliferation; Epithelial Cells; Exposure to; Fibrosis; Flow Cytometry; Functional disorder; Generations; Genes; Genetic Transcription; Goals; Human; Immunology; In Vitro; Inflammation; Inflammatory Response; Injury; Knockout Mice; Knowledge; Laboratories; Lead; Length; Lung; Lung Transplantation; Lung diseases; Malignant Neoplasms; Mediator of activation protein; Mentors; Mesenchymal; Mesenchyme; Modeling; Morphogenesis; Mus; Mutation; Paracrine Communication; Pathogenesis; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Phenotype; Physicians; Play; Population; Prevalence; Profibrotic signal; Prognosis; Protein Secretion; Proteins; Proteomics; Pulmonary Fibrosis; Regenerative capacity; Research; Resource Allocation; Risk Factors; Role; Scientist; Signal Pathway; Signal Transduction; Source; Stromal Cell-Derived Factor 1; Telomere Maintenance; Telomere Maintenance Gene; Testing; Therapeutic; Time; Tissues; Training; Transplantation; United States; Universities; alveolar epithelium; autocrine; base; career; cell type; chemokine; epithelial stem cell; fibrotic lung; genome editing; idiopathic pulmonary fibrosis; improved; in vivo; migration; mouse model; novel; novel therapeutics; paracrine; prevent; pulmonary function; pulmonary function decline; response; senescence; skills; telomere; theories

Project Summary/Abstract: Idiopathic pulmonary fibrosis (IPF) is a progressive, fibrosing lung disease for which there is no cure. IPF is associated with aging and will likely become more common as our population ages. The pathophysiology of IPF remains incompletely understood, but the alveolar epithelium, specifically the senescent alveolar epithelium, has recently been implicated in this disease. Telomeres are DNA and protein caps on the ends of chromosomes. Short telomeres are a known risk factor for IPF, and mutations in telomere maintenance genes cause IPF. In the setting of telomere dysfunction, alveolar epithelial cells (AECs) rather than dying, preferentially become senescent. Senescent AECs have been shown to secrete pro-survival and pro-fibrotic proteins. This is known as the senescence-associated secretory phenotype (SASP). Multiple SASP proteins have been shown to be capable of inducing their own secretion through autocrine (feed-forward) pathways and to also signal in the traditional paracrine fashion to bystander, non-senescent cells. CXCL12, a SASP protein, has previously been shown to be capable of both autocrine and paracrine signaling in an AEC-like cell line, but the downstream transcriptional and proteomic consequences have not been fully explored. CXCL12 has also been shown to play an important role in lung morphogenesis, but the major cell-type of origin of CXCL12 is not known. The main objective of this proposal is to determine the role of CXCL12 as an autocrine and paracrine mediator originating from a senescent alveolar epithelium and whether loss of CXCL12 signaling from the pulmonary epithelium prevents the fibrotic response. The downstream signals CXCL12 generates on the alveolar epithelium itself will be explored in depth. Aim 1 will utilize a novel conditionally senescent alveolar epithelial-like cell line to explore the consequences of autocrine and paracrine CXCL12 signaling onto the epithelium itself. Aim 2 will seek to determine the function of pulmonary epithelium-derived CXCL12 in a mouse model of pulmonary fibrosis. The knowledge gained from the completion of these studies may promote further research into the role of the alveolar epithelium in IPF and influence the allocation of resources toward the development of CXCL12 pathway-based therapeutics for this disease. Furthermore, this project will provide the applicant the opportunity to develop expertise in lung epithelial cell biology and immunology. The training plan will promote acquisition of advanced laboratory skills including flow cytometry, CRISPR/Cas genome editing, proteomics, and multiple elements of animal modeling. Additionally, didactic courses have been selected to supplement the hands-on training received and promote the advancement of the applicant’s career. Combined with close mentoring and the robust research environment at the University of Pittsburgh, this proposal will support the candidate’s development as an independent physician-scientist.

项目概要/摘要： 特发性肺纤维化（IPF）是一种进行性纤维化肺病，目前尚无治愈方法。IPF是 与老龄化有关，随着人口老龄化，这种情况可能会变得更加普遍。的病理生理学 IPF仍不完全清楚，但肺泡上皮细胞，特别是衰老的肺泡上皮细胞， 上皮细胞，最近被牵连在这种疾病。端粒是DNA和蛋白质帽的末端， 染色体短端粒是IPF的已知风险因素，端粒维持基因突变 导致IPF。在端粒功能障碍的情况下，肺泡上皮细胞（AEC）不是死亡， 优先变得衰老。衰老的AEC已经显示出分泌促存活和促纤维化的 proteins.这被称为衰老相关分泌表型（SASP）。多种SASP蛋白 已经显示能够通过自分泌（前馈）途径诱导其自身分泌， 以传统的旁分泌方式向旁观者非衰老细胞发出信号。CXCL 12，SASP蛋白， 先前已证明在AEC样细胞系中能够进行自分泌和旁分泌信号传导，但 下游转录和蛋白质组学的结果还没有被充分研究。CXCL 12还 CXCL 12在肺形态发生中起重要作用，但CXCL 12起源的主要细胞类型不是 知道的该建议的主要目的是确定CXCL 12作为自分泌和旁分泌的作用。 介体来源于衰老的肺泡上皮细胞，以及CXCL 12信号转导是否从 肺上皮阻止纤维化反应。下游信号CXCL 12生成在 肺泡上皮本身将被深入研究。目的1将利用一种新的条件性衰老肺泡 上皮样细胞系，以探索自分泌和旁分泌CXCL 12信号转导对细胞的影响。 上皮细胞本身。目的2将寻求确定小鼠肺上皮来源的CXCL 12的功能 肺纤维化模型。完成这些研究所获得的知识可能会进一步促进 研究肺泡上皮在IPF中的作用，并影响资源分配， 开发用于这种疾病的基于CXCL 12通路的疗法。此外，该项目将提供 申请人有机会发展肺上皮细胞生物学和免疫学方面的专业知识。培训计划 将促进获得先进的实验室技能，包括流式细胞术，CRISPR/Cas基因组编辑， 蛋白质组学和动物模型的多种元素。此外，还选择了教学课程， 补充所接受的实践培训，并促进申请人的职业发展。组合 在匹兹堡大学的密切指导和强大的研究环境下，这项提议将 支持候选人作为独立的物理学家和科学家的发展。