The impact of the HIV reservoir on pulmonary myeloid cells: virology, phenotype, and function

HIV 储存库对肺髓细胞的影响：病毒学、表型和功能

基本信息

批准号：
10083756
负责人：
Joshua Vasquez
金额：
$ 19.12万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-08 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10083756
关键词：
Address Affect Age Alveolar Alveolar Macrophages Antibodies Area Award Bioinformatics Biological Assay Biometry Blood capillaries CD14 gene CD4 Positive T Lymphocytes CD80 gene CD86 gene California Cell Count Cells Cellular biology Chronic Chronic Obstructive Airway Disease Clinical Communicable Diseases Computer Analysis Consequences of HIV Coupled Critical Care Cytometry DNA Data Defect Development Disease Disease Progression Enrollment Environment FCGR3B gene Fellowship Frequencies Functional disorder General Hospitals General Population Goals HIV HIV Infections Human Immune System Diseases Immunologic Techniques Immunologist Immunology In Situ Hybridization Individual Inflammasome Inflammation Inhalation Innate Immune System Interleukin-1 beta Interleukin-18 International Investigation Laboratories Liquid substance Lung Lung Inflammation Lung diseases Measures Mediating Medicine Mentored Research Scientist Development Award Mentors Mentorship Methods Myeloid Cells Nucleic Acids Observational Study Organ Participant Pathogenesis Pathology Patients Phagocytosis Phenotype Pneumonia Pulmonary Inflammation Pulmonology RNA Records Research Risk Sampling San Francisco Scientist Seminal Signal Pathway Specialist Standardization T-Lymphocyte Time Tissues Tobacco smoke Toxin Training Transforming Growth Factor beta Translational Research Universities Vaccines Viral Virus Replication Work antiretroviral therapy body system career comorbidity cytokine high dimensionality immunomodulatory therapies novel novel therapeutics professor programs receptor skills systemic inflammatory response targeted treatment therapeutic development translational scientist virology

项目摘要

PROJECT SUMMARY/ABSTRACT This is an application for a K01 award for Dr. Joshua Vásquez, MD, Assistant Professor in the Division of Experimental Medicine and the Division Pulmonary and Critical Care Medicine at the University of California at San Francisco who is establishing himself as a clinician-scientist in HIV immunology. His goal is to apply his pulmonary medicine background from a clinical fellowship to study the mechanisms that underlie pulmonary inflammation and immune dysfunction in treated HIV disease. This award will provide him with the support to accomplish the following goals: (1) to characterize the pulmonary reservoir of HIV and (2) to determine whether phenotypic and functional defects persist in alveolar macrophages responsible for patrolling the alveolar- capillary barrier, despite antiretroviral therapy, particularly among those with low CD4+ T cell nadirs. To achieve these goals, he will have four co-mentors who each have unique strengths and established track records of productive scientific investigation and mentorship of research fellows. His primary mentor is Dr. Peter Hunt, the interim chief of the Division of Experimental Medicine at UCSF/Zuckerberg San Francisco General Hospital, and an internationally-recognized expert in HIV translational immunology, specifically the mechanisms and consequences of chronic inflammation during treated HIV disease. Dr. Vasquez will also work with co-mentors Dr. Joseph (Mike) McCune, a preeminent immunologist who has conducted many seminal studies in HIV pathogenesis; Dr. Clifford Lowell, Chair of Laboratory Medicine and a recognized expert on intracellular signaling pathways regulating inflammation in the innate immune system; and Dr. Laurence Huang, an internationally-recognized expert in the pulmonary complications of HIV disease. He has also engaged active collaborators who will continue to provide focused support in the areas of: HIV tissue reservoir assessment by PCR (Dr. Steven Yukl), HIV-associated tissue pathology (Dr. Zoltan Laszik), alveolar macrophage immunology (Dr. Mehrdad Arjomandi), biostatistics (Dr. Peter Bacchetti), pulmonary immunology (Dr. Prescott Woodruff), as well as mass cytometry and high dimensional computational analysis (Dr. Matthew Spitzer). As a part of this award, he will pursue additional training in translational research, immunology methods, and bioinformatics. Leveraging access to unique patient samples, he will apply existing and novel immunologic techniques to determine how alveolar macrophage programs are altered in the setting of HIV disease. The results of these studies should be widely applicable to our understanding of the tissue immunology of other common diseases and be useful to guide the development of immunomodulatory therapies targeted at myeloid cells. Ultimately, the training and research plans outlined here will support his transition from being a basic immunologist and clinical pulmonary/critical care specialist to being a translational researcher equipped with the skills to pursue an independent career focused on elucidating the fundamental principles of myeloid cell biology and informing the development of therapeutics and vaccines for infectious diseases.

项目概要/摘要这是医学博士、医学博士、助理教授 Joshua Vásquez 的 K01 奖申请加州大学实验医学部以及肺科和重症监护医学部旧金山正在将自己打造成艾滋病毒免疫学领域的临床科学家，他的目标是应用他的研究成果。来自临床研究的肺医学背景，研究肺的机制该奖项将为他提供治疗艾滋病毒疾病中的炎症和免疫功能障碍的支持。完成以下目标：(1) 描述 HIV 肺部储存库的特征，以及 (2) 确定是否负责巡逻肺泡的肺泡巨噬细胞中持续存在表型和功能缺陷尽管进行了抗逆转录病毒治疗，但毛细血管屏障仍然存在，尤其是在 CD4+ T 细胞最低水平的患者中。为了实现这些目标，他将有四位共同导师，每一位都有独特的优势并建立了良好的记录他的主要导师是彼得·亨特博士，他富有成效的科学研究和对研究员的指导。加州大学旧金山分校/扎克伯格旧金山综合医院实验医学科临时主任，以及国际公认的艾滋病毒转化免疫学专家，特别是其机制和 Vasquez 博士还将与共同导师一起研究艾滋病毒治疗过程中慢性炎症的后果。 Joseph (Mike) McCune 博士是一位杰出的免疫学家，对艾滋病毒进行了许多开创性的研究发病机制；Clifford Lowell 博士，检验医学主席和公认的细胞内专家调节先天免疫系统炎症的信号通路；以及 Laurence Huang 博士，他是国际公认的艾滋病毒肺部并发症专家。合作者将继续在以下领域提供重点支持： HIV 组织储存库评估 PCR（Steven Yukl 博士）、HIV 相关组织病理学（Zoltan Laszik 博士）、肺泡巨噬细胞免疫学（Mehrdad Arjomandi 博士）、生物统计学（Peter Bacchetti 博士）、肺免疫学（Prescott Woodruff 博士）、以及质谱流式分析和高维计算分析（Matthew Spitzer 博士）。获奖后，他将继续接受转化研究、免疫学方法和生物信息学方面的额外培训。利用独特的患者样本，他将应用现有的和新颖的免疫学技术确定肺泡巨噬细胞程序在艾滋病毒疾病中如何改变这些结果。研究应该广泛适用于我们对其他常见疾病的组织免疫学的理解最终有助于指导针对骨髓细胞的免疫调节疗法的开发。这里概述的培训和研究计划将支持他从基础免疫学家过渡到临床肺部/重症监护专家成为一名具备追求技能的转化研究员一个独立的职业，专注于阐明骨髓细胞生物学的基本原理并提供信息传染病治疗方法和疫苗的开发。