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

肥胖和脂肪细胞在抗逆转录病毒治疗免疫激活中的作用

• 批准号: 8686591
• 负责人: John Koethe
• 金额: $ 11.94万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-13 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8686591
• 关键词: Academic Medical Centers; Acquired Immunodeficiency Syndrome; Adipocytes; Adipose tissue; Adult; Affect; Apoptosis; Award; Biological; Biological Markers; Biology; Biometry; Blood Vessels; Body Composition; Body mass index; C-reactive protein; CD4 Positive T Lymphocytes; CD8B1 gene; Cardiovascular Diseases; Cell Proliferation; Cell physiology; Cells; Cessation of life; Chronic; Chronic Disease; Clinical; Clinical Research; Clinical Sciences; Clinical Trials; Communicable Diseases; Comorbidity; Control Groups; Cross-Sectional Studies; DEXA; Data; Development; Disease Marker; Enrollment; Environment; Epidemic; Epidemiology; Extramural Activities; Foundations; Funding; Funding Mechanisms; Future; Goals; HIV; HIV Infections; HLA-DR Antigens; Health; Health Expenditures; Human; Hypertension; Immune; Immune system; Immunologist; Immunology; In Vitro; Individual; Inflammation; Inflammatory; Institutes; Interleukin-6; Intervention; Intervention Trial; K-Series Research Career Programs; Laboratory Research; Leptin; Life Style; Link; Lymphocyte; Lymphocyte Activation; Lymphocyte Function; Master of Science; Measures; Medicine; Mentored Patient-Oriented Research Career Development Award; Mentors; Metabolic Diseases; Monitor; National Institute of Allergy and Infectious Disease; Non obese; Obesity; Overweight; Participant; Pathogenesis; Pathway interactions; Persons; Physicians; Process; Program Development; Public Health; Publishing; Recovery; Research; Research Methodology; Research Personnel; Research Support; Resources; Risk; Risk Factors; Role; Scanning; Scientist; Series; Serum; Sodium; Specimen; Surveys; T-Cell Activation; T-Lymphocyte; Training; Translational Research; Treatment outcome; United States; Universities; adaptive immunity; adipocyte biology; adipokines; antiretroviral therapy; base; cardiovascular disorder risk; career; cohort; cytokine; design; immune activation; immune function; improved; in vivo; laboratory facility; mortality; multidisciplinary; nutrition; programs; prospective; reconstitution; research study; sedentary; skills; success; vasoconstriction

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.

描述（由申请人提供）：候选人具有深厚的流行病学背景，他在范德比尔特大学开发了一个研究领域，研究营养对艾滋病毒治疗结果的影响。他在其领域发表了多项原创研究，并参加了范德比尔特临床研究理学硕士项目（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，以实现获得免疫学专业知识和实验室研究技能的短期目标。这将使他在转化研究方面打下坚实的基础，从而实现成为一名独立研究者的长期目标，研究艾滋病毒免疫学、脂肪组织生物学和抗逆转录病毒治疗 (ART) 并发症之间的生物学机制。引入有效的联合抗逆转录病毒疗法来治疗艾滋病毒感染大大降低了艾滋病相关疾病的死亡率，但这种成功却因几种心血管和代谢疾病的较高发病率而受到影响，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，治疗后的艾滋病毒感染和过量的脂肪组织都会促进类似的免疫激活变化，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后的艾滋病毒和过量脂肪组织的影响是否是协同作用或添加剂。候选人将使用多方面的方法来研究过多的脂肪组织和经过治疗的艾滋病毒对先天免疫激活标记物的影响，这些标记物是公认的代谢和心血管疾病危险因素，以及与免疫恢复减少有关的细胞免疫激活标记物。在接受长期抗逆转录病毒治疗的艾滋病毒感染成年人的前瞻性队列中，代表了从瘦到肥胖的肥胖范围，以及未感染者的对照组。除了这项临床研究外，候选人还将进行一系列转化实验来研究 脂肪因子和脂肪细胞生物学的其他方面改变 T 细胞功能和促进细胞免疫激活。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途径，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越环境有利于候选人发展成为一名成功的独立转化研究者。他有机会接触多学科的导师小组，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先者合作。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、富有成效的研究生涯方面有着良好的记录。 Timothy Sterling 博士是国际公认的艾滋病毒专家，也是 NIAID K24 资助的接受者，用于指导转化研究的年轻研究人员。 Spyros Kalams 博士是一位卓有成就的免疫学家，也是范德比尔特 HIV 免疫发病机制核心实验室的主任（候选人将在该实验室接受实验室研究方法方面的实践、密切监控的培训）。 David Harrison 博士是血管生物学和高血压领域的领先研究员，研究领域包括活化 T 细胞对血管收缩和钠潴留的影响。此外 拥有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转化科学奖 (CTSA) 提供的独特资源，包括临床研究中心、范德比尔特临床和转化研究所，以及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师科学家发展计划对候选人进行投资，支持他的研究，这是一个竞争激烈的校内资助机制，充当校外资助的“桥梁”（即K23奖励机制）。慢性艾滋病毒感染的管理和肥胖流行是 21 世纪公共卫生面临的两大挑战。该候选人的研究计划将通过确定脂肪组织与心血管和代谢疾病发病机制以及免疫重建不良的发病机制中涉及的炎症和免疫过程之间的联系机制和途径，为艾滋病毒研究领域做出重大和变革性的贡献。该奖项将使候选人能够开发转化研究方面的新技能，产生与人类健康直接相关的研究成果以及未来 R01 资助的研究的设计，并使他能够成功过渡为一名独立且富有成效的研究者。