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

描述(由申请人提供)：应聘者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营养对艾滋病毒治疗结果的影响的利基研究。他在自己的领域发表了几项原创性研究，并参加了范德比尔特临床调查理学硕士项目(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，以实现他在免疫学和实验室研究技能方面获得专业知识的短期目标。这将使他在翻译研究方面建立坚实的基础，从而实现他的长期目标，即成为一名独立研究员，研究将艾滋病毒免疫学、脂肪组织生物学和抗逆转录病毒疗法(ART)并发症联系起来的生物机制。引入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，但这一成功受到了几种心血管和代谢性疾病的较高发病率的影响，这些疾病通常与肥胖或久坐的生活方式有关。目前的证据表明，经过治疗的艾滋病毒感染和过度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病的发展有关，但目前几乎没有数据表明经过治疗的艾滋病毒感染和过度肥胖的影响是协同作用还是相加的。候选人将使用多方面的方法来调查过剩的脂肪组织和经过治疗的艾滋病毒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，以及与免疫恢复降低有关的细胞免疫激活标志物，在接受长期抗逆转录病毒治疗的预期HIV感染成年人队列和对照组中，这些前瞻性队列代表了从瘦到肥胖的各种肥胖症。除了这项临床研究外，候选人还将进行一系列转换实验，以研究 脂肪细胞生物学中脂肪因子等方面在改变T细胞功能和促进细胞免疫激活中的作用。该项目的目标是确定与未来R01支持的干预试验的设计直接相关的目标路径，以通过最大限度地减少非艾滋病相关的并存以及最大限度地促进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出色环境有利于候选人成为一名成功的、独立的翻译研究员。他有机会接触到一个多学科的导师小组，并有机会与传染病、肥胖症、免疫学和心血管疾病研究领域的世界领导者合作。他得到了共同导师的支持，这些导师在指导受训者在学术医学方面取得成功、富有成效的研究生涯方面有着良好的记录。蒂莫西·斯特林博士是一位国际公认的艾滋病毒专家，也是NIAID提供的K24资金的接受者，用于指导年轻的研究人员进行翻译研究。Spyros Kalams博士是一位有成就的免疫学家，也是Vanderbilt HIV免疫病理学核心实验室的主任(候选人将在那里接受实验室研究方法的实践和密切监控的培训)。大卫·哈里森博士是血管生物学和高血压领域的领军人物，包括激活的T细胞对血管收缩和钠滞留的影响。除了……之外 凭借最先进的实验室设施和技术资源，候选人可以使用范德比尔特临床和翻译科学奖(CTSA)提供的独特资源，包括临床研究中心、范德比尔特临床和翻译研究所以及临床和翻译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这位候选人的研究，这是一种竞争激烈的校内资助机制，是通往校外资助的“桥梁”(即K23奖励机制)。管理慢性艾滋病毒感染和肥胖症流行是21世纪公共卫生面临的两大挑战。候选人的研究计划将对艾滋病毒研究领域做出重大和变革性的贡献，确定将脂肪组织与炎症和免疫过程联系起来的机制和途径，这些过程与心血管和代谢疾病以及免疫重建不良的发病机制有关。这一奖项将允许候选人发展新的翻译研究技能，产生与人类健康直接相关的研究成果，并设计未来由R01资助的研究，并使他能够成功地过渡到一名独立和多产的研究人员。 项目简介：美国艾滋病毒感染者超重的比例正在上升。过多的脂肪组织可能会阻碍HIV治疗时免疫功能的恢复，并进一步增加长期抗逆转录病毒治疗相关的代谢和心血管疾病的风险。更好地了解连接脂肪组织、免疫系统和抗逆转录病毒治疗的负面影响的生物机制，将有助于设计未来的干预措施，以改善艾滋病毒治疗结果并减少卫生保健支出。

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. PROJECT NARRATIVE: The proportion of persons with HIV infection in the United States who are also overweight is rising. Excess adipose tissue may hinder the recovery of immune function on HIV treatment and further increase the risk of metabolic and cardiovascular diseases associated with long-term antiretroviral therapy. An improved understanding of the biological mechanisms linking adipose tissue, the immune system, and the negative effects of antiretroviral therapy will help design future interventions to improve HIV treatment outcomes and reduce health care expenditures.