Targeting HSC-derived Circulating Fibroblast Precursors in Pulmonary Fibrosis

靶向 HSC 衍生的循环成纤维细胞前体治疗肺纤维化

• 批准号: 9275406
• 负责人: AMANDA C. LARUE
• 金额: --
• 依托单位: RALPH H JOHNSON VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-10-01 至 2017-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9275406
• 关键词: Age; Airborne Particulate Matter; Alveolar; Architecture; Autologous; Automobile Driving; Biological Markers; Blood Circulation; Bone Marrow; Breathing; Cell Transplantation; Cells; Chronic; Chronic lung disease; Clonal Hematopoietic Stem Cell; Clone Cells; DDR2 gene; Data; Development; Diagnosis; Disease; Disease Progression; Dust; Effector Cell; Environmental Hazards; Epithelial Cell Proliferation; Evaluation; Exposure to; Extracellular Matrix; FDA approved; Fibroblasts; Fibrosis; Flow Cytometry; Gases; Goals; Gulf War; Health; Hematopoietic stem cells; Heterogeneity; Human; In Vitro; Incidence; Lead; Lung; Lung diseases; Medical; Methods; Mission; Modeling; Molecular; Mus; Myofibroblast; PTPRC gene; Particulate; Patients; Phenotype; Physiologic pulse; Population; Population Heterogeneity; Pulmonary Fibrosis; Pulse Oximetry; Recruitment Activity; Respiration Disorders; Risk; Role; Silicon Dioxide; Soldier; Staining method; Stains; Testing; Therapeutic; Therapeutic Effect; Tissues; Transplantation; Treatment Effectiveness; Treatment Efficacy; Veterans; Xenograft Model; alveolar type II cell; base; effective therapy; enhanced green fluorescent protein; environmental chemical; hazard; human disease; improved; in vitro testing; in vivo; insight; microCT; monocyte; new therapeutic target; novel; paracrine; particle; peripheral blood; persistent symptom; progenitor; public health relevance; reconstitution; response; therapeutic target

DESCRIPTION (provided by applicant): Exposure to environmental and chemical hazards is thought to be a major contributing factor to Gulf War illness (GWI) (US Dept VA). Of particular concern for Gulf War Veterans is chronic inhalation of sand, dust and airborne particulates while in theater which pose significant risk for development of respiratory diseases including pulmonary fibrosis (PF). PF is a chronic lung disease characterized by accumulation of extracellular matrix (ECM), destruction of normal lung architecture, and decreased capacity for gas exchange. The activated fibroblast is the primary effector cell in PF. However, targeting activated fibroblasts is challenging due, in part, to the heterogeneity of the population. This heterogeneity is thought to reflect the multiple proposed origins of fibroblasts, making it essential to elucidate the role of fibroblasts from all origins i PF. Using mice whose bone marrow was reconstituted by a clonal population of cells derived from a single enhanced green fluorescent protein positive (EGFP+) hematopoietic stem cell (HSC), we have demonstrated an HSC origin for fibroblasts and activated fibroblasts in multiple tissues. We also identified a CD45+DDR2+ HSC-derived circulating fibroblast precursor (CFP) in peripheral blood of mice and humans that is related to the monocyte, gives rise to activated fibroblasts, produces pro-fibrotic factors, increases with disease, and can be therapeutically targeted. Using a silica model of PF that mimics particulate exposure in Veterans of the Gulf War, we have shown that CFPs increase in circulation with PF and traffic to the fibrotic lung. Together, our findings support the hypothesis that HSC-derived CFPs are critical to progression of PF and can be targeted to inhibit fibrotic progression. This will be tested using our novel clonal HSC cell transplantation method in conjunction with a silica instillation PF model in three Specific Aims. Aim 1 will temporally examine CFP contribution to silica-induced PF and potential of CFPs to serve as an early biomarker for disease and/or response to therapy (Aim 1). Studies in Aim 2 will elucidate mechanisms regulating participation, activation and pro-fibrotic effects of CFPs. Finally, we will examine the effect of therapeutically targeting this unique fibrotic progenitor using both mouse-to-mouse transplant and human-to-mouse xenograft models to demonstrate that inhibition of CFPs can reduce progression of silica-based fibrosis and is applicable to human disease (Aim 3). The proposed studies are paradigm shifting in that most studies focus on targeting the activated fibroblast or relatively mature fibrocyte in fibrosis, whie our data suggests that the more primitive CFP may provide a more effective therapeutic target. These studies are significant in that they are the first to conduct flow cytometric, immunohistochemical, molecular, and functional evaluation of HSC-derived CFPs and their contribution to PF. It is suggested that the number of Veterans diagnosed with Gulf War Illness, including respiratory diseases, is grossly underestimated. As GWI is better defined and the Veteran population serving in the Gulf ages, we expect to see an increased incidence of PF in the Veteran population. Studying early markers of PF is of great relevance to the VA mission as it will allow us to better detect early signs of PF in patients, potentially using CFPs as a biomarker, to dramatically improve effectiveness of treatment prior to loss of normal lung architecture and function. Therefore, these studies have the potential to directly impact Gulf War Veterans' health as well as have far-reaching application to Veterans with multiple types of fibrotic disease.

描述（由申请人提供）：

项目成果

Physical and elemental analysis of Middle East sands from recent combat zones.

对来自最近战区的中东沙子进行物理和元素分析。

• DOI: 10.1080/08958378.2020.1766602
• 发表时间: 2020
• 期刊: Inhalation toxicology
• 影响因子: 2.1
• 作者: McDonald,LindsayT;Christopher,StevenJ;Morton,SteveL;LaRue,AmandaC
• 通讯作者: LaRue,AmandaC

Experimental respiratory exposure to putative Gulf War toxins promotes persistent alveolar macrophage recruitment and pulmonary inflammation.

实验性呼吸道暴露于假定的海湾战争毒素会促进肺泡巨噬细胞持续招募和肺部炎症。

• DOI: 10.1016/j.lfs.2021.119839
• 发表时间: 2021
• 期刊: Life sciences
• 影响因子: 6.1
• 作者: Powers,AmyA;Jones,KatherineE;Eisenberg,SethH;Rigatti,LoraH;Ryan,JohnP;Luketich,JamesD;Lotze,MichaelT;LaRue,AmandaC;Dhupar,Rajeev;Soloff,AdamC
• 通讯作者: Soloff,AdamC