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

基本信息

批准号：
8897929
负责人：
Heather Winona Stout Delgado
金额：
$ 13.74万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8897929
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 adaptive immunity 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

项目摘要

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（由申请人提供）：随着人口老龄化和慢性肝病成为发病率和死亡率的越来越重要的原因，迫切需要提高我们对慢性病毒感染期间先天和适应性免疫反应动态的理解，以及这些反应对病毒清除的关系。由于先天免疫反应是针对病原体的第一道防线，因此必须阐明衰老如何改变先天免疫力并促进慢性病毒持久性。血囊性树突状细胞（PDC）在检测异物病原体中起关键作用，并代表了暴露于病毒感染后1型IFN的主要来源或类似Toll-like受体9（TLR9）或TLR7特异性配体。该提案的目的是检查慢性病毒感染对PDC细胞功能的影响，以及这些作用如何有助于病毒持久性和对继发感染的敏感性。我的博士学位和博士后研究的重点是病毒感染期间先天和适应性免疫反应，从而获得了令人印象深刻的出版记录。我在当前的研究建议中概述了研究技术。尽管我的初步工作集中在急性病毒感染上，但我的提议旨在研究慢性病毒感染如何影响先天的抗病毒药免疫反应随着衰老而产生。这个新的调查领域对越来越多的慢性病毒感染负担的老龄化人群具有重要的临床相关性。该提案中概述的实验结果将洞悉衰老对慢性病毒感染期间先天免疫反应的影响。最后，我设想拟议的工作是作为弹簧董事会，该委员会将启动作为独立资助的科学家的职业。在继续直接计划和执行实验时，我对生物医学研究进行批判性思考的能力将得到进一步完善，并将导致其他假设，这些假设可以作为未来赠款应用程序的一部分进行测试（例如R01）。我坚持认为，我有才能和动力成为成功的衰老研究人员，我坚信我在衰老和免疫方面的工作将有助于理解和治疗慢性病毒感染。获得K01指导的研究科学家发展奖将使我能够实现我的主要职业目标，即成为衰老和病毒免疫领域的专家和领导者，他们通过关注衰老和改变免疫反应之间的复杂关系，将做出重要的研究贡献，最终将最终转化为改善老年人的功能状况。在我的主要指导团队的指导下，我构建了以下职业发展活动，以支持我的主要职业目标。通过我迄今为止的学术培训和工作经验，我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，我计划专注于培训的运营方面，将时间中最大的时间用于动手研究培训，并得到了针对目前不足的特定领域的高度重点的教学培训的补充。因此，拟议的职业发展计划旨在为我提供所需的工具，以发展成老化领域的高度竞争，独立的研究人员。除了从执行研究计划和与指导团队互动的经验外，我还建议在奖励期的前两年中进行特定的课程工作，这将帮助我短期和长期目标。