Investigating paclitaxel treatment in a pre-clinical model of Schistosoma-pulmonary hypertension

研究血吸虫肺动脉高压临床前模型中的紫杉醇治疗

• 批准号: 9419493
• 负责人: Brian Barkley Graham
• 金额: $ 2.61万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-22 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9419493
• 关键词: Accounting; Amplifiers; Animal Model; Antigen-Presenting Cells; Antigens; Aspergillus; Autoimmune Diseases; Biological Models; Blood Vessels; CD4 Positive T Lymphocytes; Cell Proliferation; Cells; Chronic; Clinical; Communicable Diseases; Data; Developed Countries; Developing Countries; Development; Disease; Etiology; Exposure to; Fractalkine; Goals; Human Pathology; Hypertension; Hypoxia; Immune; Immune Tolerance; Immune system; Immunity; Immunotherapy; Inflammation; Inflammatory; Interleukin-1; Interleukin-13; Interleukin-4; Link; Lung; Mediating; Modeling; Molecular; Monocrotaline; Mus; Natural Immunity; Paclitaxel; Parasites; Parasitic Diseases; Parasitic infection; Pathogenesis; Pathogenicity; Patients; Phenotype; Physiologic intraventricular pressure; Population; Pre-Clinical Model; Predisposition; Process; Production; Publications; Pulmonary Hypertension; Pulmonary Pathology; Pulmonary artery structure; Rattus; Receptor Cell; Recruitment Activity; Regulatory T-Lymphocyte; Role; SU 5416; Schistosoma; Schistosoma mansoni; Schistosomiasis; Scleroderma; Series; Signal Transduction; Source; Stimulus; T-Lymphocyte; Transforming Growth Factor beta; Uncertainty; Vaccination; Vascular Diseases; Vascular remodeling; adaptive immunity; cytokine; egg; experimental study; human disease; macrophage; monocyte; mouse model; new therapeutic target; novel strategies; prevent; pulmonary arterial hypertension; reconstitution; research study; response; uptake

PROJECT SUMMARY / ABSTRACT The recognition that inflammation has important roles in the pathogenesis of pulmonary arterial hypertension (PAH) arises from evidence that autoimmune and infectious diseases are associated with the development of PAH; inflammation can generate experimental pulmonary hypertension (PH); and perivascular inflammation is present in the pathology of human PAH and animal models of PH. However, whether inflammation is causal, an amplifier of alternative triggering mechanisms, or an epiphenomenon remains unclear. Prior studies on the role of T cells in disease pathogenesis have generated data of unclear relevance to PAH: Th2 and Th17 cells are detrimental in Aspergillus-exposed and chronically hypoxic mice, respectively, while regulatory T cells (Tregs) are protective in rats treated with SU5416 or monocrotaline. The translational application of these data is hampered by limited inflammation in the chronic hypoxia model and unclear mechanisms linking inflammation to vascular remodeling. We propose to interrogate a model system with a relevant antigen that activates specific Type 2 immunity; a perivascular compartment in which there is antigen uptake and presentation, cell proliferation and recruitment; and molecular mechanisms involving TGF-β1 resulting in pulmonary artery remodeling. We employ a mouse model triggered by the parasite Schistosoma mansoni, which reproduces key phenotypes of likely the most common cause of PAH worldwide. Our proposal seeks to identify the precise role of antigen- specific CD4 T cells as the source of IL-4 and IL-13; how this population arises, expands, and is activated; and its impact on monocyte recruitment and TGF-β activation. We hypothesize that exposure to Schistosoma egg antigens results in clonogenic Th2 CD4 T cell activation and proliferation, leading to production of IL-4 and IL-13; this prototypic Th2 response recruits Ly6C+ monocytes causing TGF-β-driven PH. Our overall goals are to determine the molecular mechanisms underlying the pathogenesis of Schistosoma-PH; identify approaches to develop immunotherapies, such as vaccination, against this parasitic disease; and to more broadly identify novel therapeutic targets in the inflammatory cascade, which may also be applicable to other inflammation-driven PAH etiologies. Specific Aim 1 is to determine that T cell IL-4 and IL-13-driven inflammation caused by Schistosoma leads to TGF-β activation and PH. In this Aim we will investigate the necessity and sufficiency of Th2-activated CD4 T cells in Schistosoma-PH using a systematic series of experiments with deficient mice and immune reconstitution, to precisely determine whether CD4-derived IL-4/IL- 13 is critical for Ly6C+ monocyte recruitment and the overproduction of active TGF-β1 which results in PH. Specific Aim 2 is to determine the Schistosoma antigen(s) taken up by antigen presenting cells that activate pathogenic, clonogenic IL-4/IL-13 producing CD4 T cells in Schistosoma-PH. In this Aim we will identify specific pathogenic Schistosoma antigens; the cells taking up, processing and presenting Schistosoma antigens to activate CD4 T cells; and the CD4 T cell receptor (TCR) repertoire indicative of clonal selection.

项目摘要/摘要