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

项目总结/摘要 这是一份K 01奖的申请书，申请人是医学博士约书亚·巴斯克斯，他是医学部的助理教授。 实验医学和加州大学肺部和重症监护医学部， 旧金山弗朗西斯科，他正在确立自己作为艾滋病毒免疫学临床科学家的地位。他的目标是应用他的 肺医学背景，来自临床研究基金会，研究肺动脉高压的机制， 炎症和免疫功能障碍。该奖项将为他提供支持， 实现以下目标：（1）表征HIV的肺部储库和（2）确定是否 表型和功能缺陷持续存在于肺泡巨噬细胞负责巡逻肺泡， 毛细血管屏障，尽管抗逆转录病毒治疗，特别是在那些低CD 4 + T细胞最低点。实现 这些目标，他将有四个共同的导师谁都有独特的优势和既定的跟踪记录， 富有成效的科学调查和研究员的指导。他的主要导师是彼得·亨特博士， 加州大学旧金山分校/扎克伯格弗朗西斯科总医院实验医学部的临时主任， 他是国际公认的艾滋病毒转化免疫学专家，特别是其机制和 在治疗HIV疾病期间慢性炎症的后果。瓦斯奎兹博士还将与共同导师 博士约瑟夫（迈克）麦克库恩，一个杰出的免疫学家谁进行了许多开创性的研究，艾滋病毒 发病机制; Clifford Lowell博士，实验室医学主席和公认的细胞内 调节先天免疫系统炎症的信号通路;和Laurence Huang博士， 国际公认的艾滋病肺部并发症专家。他还积极参与 合作者将继续在以下领域提供重点支持： 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 (Dr. Mehrdad Arjomandi），生物统计学（Peter Bacchetti博士），肺免疫学（Prescott Woodruff博士）， 以及质谱细胞术和高维计算分析（Matthew Spitzer博士）。作为其中的一部分 获得该奖项后，他将继续在转化研究、免疫学方法和生物信息学方面进行额外的培训。 利用独特的患者样本，他将应用现有的和新的免疫技术， 确定肺泡巨噬细胞程序如何在艾滋病的背景下改变。的结果予以 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。 并可用于指导靶向骨髓细胞的免疫调节疗法的开发。最后， 这里概述的培训和研究计划将支持他从基础免疫学家的转变， 临床肺/重症监护专家成为一个翻译研究人员配备的技能，追求 一个独立的职业生涯，专注于阐明骨髓细胞生物学的基本原则，并为 传染病的治疗和疫苗的发展。

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.