Aging with Chronic Viral Infections and the Impact on Innate Immune Responses

慢性病毒感染引起的衰老及其对先天免疫反应的影响

• 批准号: 8309075
• 负责人: Heather Winona Stout Delgado
• 金额: $ 13.74万
• 依托单位: LOVELACE BIOMEDICAL & ENVIRONMENTAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8309075
• 关键词: Academic Training; Acute; Acute Hepatitis C; Affect; Age; Aging; Antiviral Agents; Applications Grants; Area; Award; Cause of Death; Cell physiology; Chronic; Chronic Active Hepatitis; Cirrhosis; Complement; Complex; Dendritic Cells; Detection; Developed Countries; Development Plans; Diagnosis; Elderly; Exposure to; Foundations; Funding; Future; Goals; Hepatitis C; Hepatitis C virus; Human Herpesvirus 2; Immune response; Immunity; Immunologics; Infection; Interferons; Investigation; Lead; Life Expectancy; Ligands; Liver Cirrhosis; Liver diseases; Mediating; Mentored Research Scientist Development Award; Mentorship; Methods; Modeling; Morbidity - disease rate; Motivation; Mus; Natural Immunity; Play; Postdoctoral Fellow; Predisposition; Primary carcinoma of the liver cells; Production; Publications; Research; Research Personnel; Research Proposals; Research Technics; Research Training; Role; Scientist; Secondary to; Side; Source; Staging; Structure; TLR7 gene; TLR9 gene; Talents; Testing; Time; Training; Translating; United States; Viral; Virus Diseases; Work; aged; aging population; career; career development; chronic liver disease; clinically relevant; design; experience; functional status; improved; insight; mortality; novel; older patient; pathogen; research study; response; secondary infection; tool

DESCRIPTION (provided by applicant): With an aging population and chronic liver disease becoming an increasingly significant cause of morbidity and mortality, there is an urgent need to improve our understanding of the dynamics of innate and adaptive immune responses during chronic viral infection and the relationship of these responses to viral clearance. As the innate immune response is the first line of defense against pathogens, it is imperative to elucidate how aging modifies innate immunity and contributes to chronic viral persistence. Plasmacytoid dendritic cells (pDCs) play a pivotal role in detection of foreign pathogens and represent a major source of type 1 IFN post exposure to viral infections or Toll-Like Receptor 9 (TLR9) or TLR7 specific ligands. The goal of this proposal is to examine the effects of chronic viral infection on pDC cell function and how these effects contribute to viral persistence and susceptibility to a secondary infection. My doctoral and post-doctoral research that focused on innate and adaptive immune responses during viral infection led to an impressive publication record. I am skilled in the research techniques outlined in my current research proposal. While my preliminary work focused on acute viral infection, my proposal aims to investigate how chronic viral infections influence innate antiviral immune responses with aging. This novel field of investigation has important clinical relevance for an aging population increasingly burdened with chronic viral infection. Results from the experiments outlined in this proposal will provide insight on the influence of aging on innate immune responses during chronic viral infections. Lastly, I envision the proposed work to serve as a spring board that will launch a career as an independently funded scientist. In continuing to directly plan and execute experiments, my ability to think critically about biomedical investigation will be further refined and will lead to additional hypotheses which can be tested as part of a future grant application (e.g., R01). I resolutely believe that I have the talent and motivation to become a successful investigator in aging and I strongly believe that my work in aging and immunity will help in the understanding and treatment of chronic viral infections. Receipt of a K01 Mentored Research Scientist Development Award will allow me to achieve my primary career goal of becoming an expert and leader in the field of aging and viral immunity, who, by focusing on the complex relationship between aging and altered immune responses, will make important research contributions that will ultimately translate into improving the functional status of older persons. Under the guidance of my primary mentorship team, I have structured the following career development activities to support my primary career goal. Through my academic training and work experiences to date, I have obtained the essential underpinnings for applying immunologic methods to aging research. Given this strong foundation, I plan to focus on the operational side of my training, spending the largest proportion of my time with hands-on research training, complemented by highly focused didactic training targeting specific areas that are currently deficient. Therefore, the proposed career development plan is designed to give me the required tools to develop into a highly competitive, independent researcher in the field of aging. In addition to the experience that I will gain from executing the research plan and interacting with the mentorship team, I have proposed specific course work through the first two years of the award period that will help me short-term and long-term goals.

描述(申请人提供)：随着人口老龄化和慢性肝病日益成为发病率和死亡率的重要原因，迫切需要提高我们对慢性病毒感染期间先天和获得性免疫反应的动态以及这些反应与病毒清除的关系的了解。由于先天免疫反应是抵御病原体的第一道防线，因此必须阐明衰老是如何改变先天免疫并促进慢性病毒持续存在的。浆细胞样树突状细胞(PDC)在检测外来病原体方面发挥着关键作用，是病毒感染或Toll样受体9(TLR9)或TLR7特异性配体暴露后产生1型干扰素的主要来源。这项建议的目的是研究慢性病毒感染对PDC细胞功能的影响，以及这些影响如何有助于病毒的持久性和对二次感染的易感性。我的博士和博士后研究重点是病毒感染期间的先天和适应性免疫反应，这导致了令人印象深刻的出版记录。我精通我目前的研究计划中概述的研究技术。虽然我的初步工作集中在急性病毒感染上，但我的提案旨在研究随着年龄的增长，慢性病毒感染如何影响先天抗病毒免疫反应。这一新的研究领域对日益加重慢性病毒感染负担的老龄化人口具有重要的临床意义。本提案中概述的实验结果将为了解衰老对慢性病毒感染期间先天免疫反应的影响提供洞察力。最后，我设想拟议中的工作将成为一个跳板，将开启独立资助科学家的职业生涯。在继续直接计划和执行实验的过程中，我对生物医学研究进行批判性思考的能力将得到进一步提高，并将产生额外的假设，这些假设可以作为未来拨款申请的一部分进行测试(例如，R01)。我坚定地相信我有天赋和动力成为一名成功的老龄研究人员，我坚信我在衰老和免疫方面的工作将有助于了解和治疗慢性病毒感染。获得K01指导研究科学家发展奖将使我实现我的主要职业目标，成为衰老和病毒免疫领域的专家和领导者，通过关注衰老和免疫反应变化之间的复杂关系，将做出重要的研究贡献，最终转化为改善老年人的功能状态。在我的主要指导团队的指导下，我组织了以下职业发展活动，以支持我的主要职业目标。通过我到目前为止的学术培训和工作经验，我已经获得了将免疫学方法应用于衰老研究的基本基础。鉴于这一强大的基础，我计划将重点放在我的培训的操作方面，将我的大部分时间花在实践研究培训上，辅之以针对当前不足的特定领域的高度专注的教学培训。因此，拟议的职业发展计划旨在为我提供必要的工具，使我发展成为老龄化领域具有高度竞争力的独立研究人员。除了我将从执行研究计划和与导师团队互动中获得的经验外，我还建议在授勋期间的头两年进行具体的课程工作，这将帮助我实现短期和长期目标。