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Role of Resident Monocytes in the Pathogenesis of Pulmonary Arterial Hypertension

常驻单核细胞在肺动脉高压发病机制中的作用

基本信息

批准号：
8821892
负责人：
Yen-Rei Andrea Yu
金额：
$ 11.94万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-15 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8821892
关键词：
Ablation Basic Science Biology Blood Vessels Cell physiology Cells Cessation of life Chronic Data Dendritic Cells Development Development Plans Diagnosis Disease Disease Progression Educational Curriculum Endothelial Cells Ensure Etiology Genetic Predisposition to Disease Goals Heart failure Human Hypoxia Hypoxia Inducible Factor Immune Immunobiology Immunology Immunotherapy Infiltration Inflammation Inflammatory Inflammatory Response Knowledge Label Laboratories Lung Mentors Mining Modeling Morbidity - disease rate Mus Mutation Myeloid Cells Oxygen Pathogenesis Patients Physicians Play Population Pulmonary artery structure Pulmonary vessels Quality of life Rattus Regulation Reporter Reporting Research Research Project Grants Role Scientist Sensory Severities Signaling Molecule Smooth Muscle Myocytes Stimulus Stress Techniques Testing Time Training Transgenic Mice Translations Vascular remodeling Writing arteriole base biobank bone morphogenetic protein receptors career development cell type design experience hypoxia inducible factor 1 improved in vivo insight interest knockout gene macrophage monocyte mortality novel pressure prevent public health relevance pulmonary arterial hypertension recombinase repaired research study response sensor skills therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Career Development Goal/Plan: The long-term goal of the applicant is to contribute to scientific knowledge and improve quality of life for patients with pulmonary arterial hypertension. The overall objective of the applicant is to become an independent physician scientist specializing in pulmonary vascular immunobiology. To achieve this objective, the applicant has designed a career development plan that incorporates the following: a curriculum involving formal classes and other didactic teachings that enhance basic science background, writing skills, and critical analysis; at least 75% protected research time with hands-on laboratory experiences to develop new technical skills; and close mentoring by accomplished physician-scientists to ensure a successful transition into independence. The proposed research project combines the applicant's background in immunology and interest in pulmonary vascular biology and will serve as a platform to develop an independent line of research. Research: Pulmonary arterial hypertension (PAH) is a group of diseases caused by abnormal remodeling and narrowing of small pulmonary arterioles, leading to elevation of pulmonary arterial pressure, right heart failure, severe hypoxia, and eventual death. Even with known treatments, mortality remains high. Better understanding of PAH pathogenesis is needed to identify potential therapeutic targets. Substantial evidence suggests that the infiltration of pulmonary vessels by myeloid cells, such as monocytes, macrophages and dendritic cells, have a critical role in the development of PAH. However, neither the specific myeloid cell population that infiltrates pulmonary arteries, nor the activity of these cells has been deter- mined. Using chronic hypoxia models of PAH, my preliminary data demonstrates that resident monocytes accumulate around the pulmonary arterioles and promote PAH. My hypothesis is that resident monocytes infiltrate pulmonary vessels and, in response to hypoxic stimuli, initiate inflammatory responses and differentiate into cells with vascular remodeling activity, thereby promoting PAH development. To test this hypothesis, we will take advantage of a novel line of transgenic mice that expresses Cre recombinase specifically in resident monocytes. Using these mice, we have developed models of 1) resident monocyte- specific fluorescent reporters, 2) inducible resident monocyte ablation, and 3) resident monocyte-specific gene knockouts. In Aim 1, we will specifically delete hypoxia-inducible factors (HIFs), the central hypoxia- sensory molecules, in resident monocytes to determine the role of resident monocytes in sensing hypoxia and PAH pathogenesis. In Aim 2, utilizing our capacity to deplete resident monocytes in vivo, we will determine the contribution of resident monocytes to both the development and progression of this disease. We expect findings from the proposed experiments will improve our insight into monocyte biology, HIF regulation, and role of resident monocytes in PAH pathogenesis.