The Role of Obesity and Adipocytes in Immune Activation on Antiretroviral Therapy

描述（由申请人提供）：候选人在流行病学方面有很强的背景，他在范德比尔特大学开发了一个研究利基，研究营养对艾滋病毒治疗结果的影响。他在自己的领域发表了几篇原创研究论文，并参加了范德比尔特临床研究科学硕士课程（2010-2012），以获得生物统计学和临床试验方面的额外培训。他正在申请K23职业发展奖，以实现他获得免疫学和实验室研究技能专业知识的短期目标。这将使他能够在转化研究方面建立坚实的基础，从而实现他的长期目标，即成为一名独立的研究人员，研究将HIV免疫学，脂肪组织生物学和抗逆转录病毒治疗（ART）并发症联系起来的生物学机制。采用有效的联合抗逆转录病毒疗法治疗艾滋病毒感染，大大降低了艾滋病相关疾病的死亡率，但这一成功却因几种通常与肥胖或久坐生活方式有关的心血管和代谢疾病的发病率较高而受到影响。目前的证据表明，治疗的HIV感染和过量的脂肪组织都促进了免疫激活的类似变化，这些变化与一系列慢性疾病的发展有关，但目前很少有数据表明治疗的HIV和过量的脂肪的影响是协同的还是相加的。候选人将使用多方面的方法来研究过量脂肪组织和治疗的HIV对先天免疫激活标志物的影响，这些标志物是公认的代谢和心血管疾病风险因素，以及与免疫恢复减少有关的细胞免疫激活标志物，在一组长期接受抗逆转录病毒治疗的HIV感染成年人中，代表了从瘦到肥胖的一系列肥胖症，对照组为未感染的个体。除了这项临床研究，候选人将进行一系列的翻译实验，以调查的机制作用， 脂肪因子和脂肪细胞生物学的其他方面在改变T细胞功能和促进细胞免疫活化中的作用。该项目的目标是确定与未来R 01支持的干预试验设计直接相关的目标途径，以通过最大限度地减少非艾滋病相关的合并症以及最大限度地提高免疫重建来改善艾滋病毒治疗结果。范德比尔特大学医学中心的优秀环境有利于候选人成为一名成功的独立翻译研究者。他有机会接触到多学科的导师，并有机会与传染病，肥胖，免疫学和心血管疾病研究领域的世界领导人合作。他得到了共同导师的支持，他们在指导学员在学术医学领域取得成功，富有成效的研究事业方面有着良好的记录。Timothy Sterling博士是国际公认的HIV专家，也是NIAID K24资助的接受者，指导年轻的研究人员进行转化研究。Spyros Kalams博士是一位有成就的免疫学家，也是范德比尔特艾滋病毒免疫病理学核心实验室的主任（候选人将在实验室研究方法方面接受实践和密切监测的培训）。大卫哈里森博士是血管生物学和高血压领域的领先研究者，包括活化T细胞对血管收缩和钠潴留的影响。除了 国家的最先进的实验室设施和技术资源，候选人有机会获得独特的资源，使之成为可能的范德比尔特临床和转化科学奖（CTSA），包括临床研究中心，范德比尔特临床和转化研究所，和临床和转化科学家发展教育计划。该大学通过为期两年的范德比尔特医生科学家发展计划支持他的研究，对候选人进行了投资，这是一个竞争激烈的校内资助机制，作为校外资助的“桥梁”（即K23奖励机制）。慢性HIV感染和肥胖症流行的管理是21世纪公共卫生面临的两大挑战。候选人的研究计划将通过确定将脂肪组织与心血管和代谢疾病以及免疫重建不良的发病机制中所涉及的炎症和免疫过程联系起来的机制和途径，为艾滋病毒研究领域做出重大和变革性的贡献。该奖项将允许候选人发展转化研究的新技能，产生与人类健康直接相关的研究成果和未来R 01资助研究的设计，并使他成功过渡到一个独立和富有成效的研究者。

DESCRIPTION (provided by applicant): The candidate has a strong background in epidemiology, and he has developed a research niche at Vanderbilt University studying the effect of nutrition on HIV treatment outcomes. He has published several original research studies in his field and enrolled in the Vanderbilt Masters of Science in Clinical Investigation program (2010-2012) to gain additional training in biostatistics and clinical trials. He is applyin for a K23 career development award to achieve his short-term goal of acquiring expertise in immunology and laboratory research skills. This will allow him to establish a strong foundation in translational research and therefore attain his long term goal of becoming an independent investigator studying the biological mechanisms that link HIV immunology, adipose tissue biology, and antiretroviral therapy (ART) complications. The introduction of effective combination ART for the treatment of HIV infection greatly reduced mortality from AIDS-related conditions, but this success has been tempered by higher rates of several cardiovascular and metabolic diseases more commonly associated with obesity or a sedentary lifestyle. Current evidence suggests both treated HIV infection and excess adipose tissue promote similar changes in immune activation that are implicated in the development of a range of chronic diseases, but at present there are few data on whether the effects of treated HIV and excess adiposity are synergistic or additive. The candidate will use a multifaceted approach to investigate the effects of excess adipose tissue and treated HIV on markers of innate immune activation that are well-established metabolic and cardiovascular disease risk factors, as well as markers of cellular immune activation implicated in reduced immune recovery, in a prospective cohort of HIV-infected adults on long-term ART representing a spectrum of adiposity from lean to obese and a control group of uninfected individuals. In addition to this clinical study, the candidate will conduct a series of translational experiments to investigate the mechanistic role of adipokines and other aspects of adipocyte biology in altering T cell function and promoting cellular immune activation. The goal of the this project is to identify target pathways directly relevant to the design of future, R01-supported intervention trials to improve HIV treatment outcomes by minimizing non-AIDS related co-morbidities as well as maximizing immune reconstitution. The outstanding environment at Vanderbilt University Medical Center is conducive to the candidate's development as a successful, independent translational investigator. He has access to a multidisciplinary group of mentors and the opportunity to collaborate with world leaders in the fields of infectious diseases, obesity, immunology, and cardiovascular disease research. He is supported by co-mentors with a proven record of guiding mentees to successful, productive research careers in academic medicine. Dr. Timothy Sterling is an internationally recognized HIV expert and the recipient of K24 funding from NIAID to mentor young investigators in translational research. Dr. Spyros Kalams is an accomplished immunologist and the Director of the Vanderbilt HIV Immunopathogenesis Core lab (where the candidate will receive hands-on, closely monitored training in laboratory research methods). Dr. David Harrison is a leading researcher in the field of vascular biology and hypertension, including the effects of activated T cells on vasoconstriction and sodium retention. In addition to state-of-the-art laboratory facilities and technical resources, the candidate has access to unique resources made possible by the Vanderbilt Clinical and Translational Science Award (CTSA), including the Clinical Research Center, the Vanderbilt Institute for Clinical and Translational Research, and the Clinical and Translational Scientist Development educational program. The university has invested in the candidate by supporting his research through the two-year Vanderbilt Physician Scientist Development Program, a highly competitive intramural funding mechanism that serves as a "bridge" to extramural funding (i.e. the K23 award mechanism). The management of chronic HIV infection and the obesity epidemic are two major 21st Century challenges for public health. The candidate's Research Plan will make a significant and transformative contribution to the HIV research field by identifying mechanisms and pathways linking adipose tissue to the inflammatory and immune processes implicated in the pathogenesis of cardiovascular and metabolic diseases and poor immune reconstitution. This award will allow the candidate to develop new skills in translational research, generate research findings with direct relevance to human health and the design of future R01-funded studies, and enable his successful transition to an independent and productive investigator.