DNA Sensing by Innate Immune Cells in Human Skin

人类皮肤中先天免疫细胞的 DNA 传感

• 批准号: 8088736
• 负责人: Todd Charles Becker
• 金额: $ 12.2万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8088736
• 关键词: Bacteria; Bacterial Infections; Biology; Cells; Commit; Communicable Diseases; Conceptions; Cutaneous; DNA; DNA Sequence; DNA receptor; Data; Dendritic Cells; Dermatologic; Dermatologist; Dermatology; Development; Disease; Etiology; Family; Fellowship; Germ Lines; Goals; Host Defense; Host Defense Mechanism; Human; Immune; Immune response; Immune system; Immunity; Immunologics; Immunology; Infection; Infectious Skin Diseases; Interferons; Interleukin-12; Investigation; Laboratories; Langerhans cell; Leprosy; Lesion; Ligands; Link; Mediating; Medicine; Mentors; Mentorship; Modeling; Mycobacterium leprae; Natural Immunity; Outcome; Pathogenesis; Pathway interactions; Patients; Pattern; Poly dA-dT; Population; Principal Investigator; Program Development; Public Health; Research; Research Personnel; Research Proposals; Residencies; Role; Short Tandem Repeat; Signal Pathway; Skin; Structure; T-Lymphocyte; TNF gene; Testing; Toll-like receptors; Training; Training Programs; Virus Diseases; Work; base; career; career development; cell type; combat; cytokine; experience; immunopathology; innate immune function; insight; macrophage; microbial; microbial host; neoplastic; novel; novel therapeutics; pathogen; programs; receptor; response; skills; skin disorder; skin lesion

DESCRIPTION (provided by applicant): This proposal describes a 5 year training program for the development of an academic career in Dermatology. The principal investigator has completed over 90% of his structured residency training in Dermatology at UCLA, and is currently expanding his scientific skills through a program committed to promoting careers in academic medicine by integrating dermatology residency training with a two-year protected postdoctoral research fellowship. This program will promote the command of innate immunology, as applied to the dermatologic infectious disease, leprosy. Dr. Robert Modlin will mentor the principal investigator's scientific development and is a recognized leader in the field of leprosy and human immunology, with current ongoing studies in his laboratory involving the mechanisms of host defense and innate immunity in skin, both of which are relevant to this proposal. The principal investigator's long-term career goal is to be an independent investigator in academic dermatology with his own laboratory. The research proposal is based upon the hypothesis that the activation of distinct DNA receptors in skin immune cells confers distinct cytokine responses, thereby determining the outcome of the immune response. The specific aims include: 1) determine the mechanisms by which recognition of DNA ligands, including those of the Mycobacterium leprae short tandem repeats, contribute to host defense in skin by innate immune cells, 2) elucidate the mechanisms of DNA recognition that determine functional responses in macrophages and dendritic cells, 3) determine the role of the specific DNA recognition pathways in leprosy. It is anticipated that the proposed studies will provide novel insight into mechanisms of innate immunity in human skin, providing new therapeutic strategies to intervene in a range of skin diseases, including those of infectious, immunologic and neoplastic etiology. CANDIDATE AND ENVIRONMENT: The principal investigator is a post-graduate researcher with doctoral training in both dermatology and immunology. The breadth of his training allowed for the conception and synthesis of this proposal, which spans the fields of innate immunity, infectious disease, and skin biology: The candidate will be under the mentorship of Robert Modlin, a world-renowned immunologlst and dermatologist at UCLA. GOALS AND CAREER DEVELOPMENT: The immediate goal will be to explore the mechanism of host DNA recognition by innate immune cells in skin according to the induction of distinct cytokine responses. This will be accomplished using leprosy as a model, with the results having broad implications for a spectrum of skin diseases. The long term goal will be to use this experience to become an established investigator who can apply these immunologic principles to gain insight and develop novel therapies for other skin diseases. RELEVANCE: The ability of innate immune cells in skin to recognize DNA is a novel immunologic mechanism that influences the innate immune response, and can be studied using leprosy as a model. Investigations in leprosy have helped establish immunologic paradigms that direct disease treatment, including type 1 and type 2 T cell immunity and the function of Toll like receptors in microbial infection. Through the work in this proposal, we will define the mechanisms by which cells of the innate immune system in skin recognize DNA patterns, leading to the induction of distinct cytokine responses that contribute to disease pathogenesis.

描述（由申请人提供）：本提案描述了一个为期5年的培训计划，为发展皮肤科的学术生涯。主要研究者已经完成了超过90%的UCLA皮肤科住院医师培训，目前正在通过一项致力于促进学术医学事业的计划来扩展他的科学技能，该计划将皮肤科住院医师培训与为期两年的受保护博士后研究奖学金相结合。该计划将促进先天免疫学的命令，适用于皮肤传染病，麻风病。Robert Modlin博士将指导主要研究者的科学发展，他是麻风病和人类免疫学领域公认的领导者，目前正在他的实验室进行的研究涉及宿主防御和皮肤先天免疫的机制，两者都与本提案有关。首席研究员的长期职业目标是成为一名独立的学术皮肤病学研究员，拥有自己的实验室。该研究提案基于以下假设：皮肤免疫细胞中不同DNA受体的激活赋予不同的细胞因子应答，从而决定免疫应答的结果。具体目标包括：1）确定识别DNA配体（包括麻风分枝杆菌短串联重复序列的DNA配体）有助于先天性免疫细胞在皮肤中的宿主防御的机制，2）阐明决定巨噬细胞和树突状细胞中的功能反应的DNA识别机制，3）确定特异性DNA识别途径在麻风中的作用。预计拟议的研究将为人类皮肤先天免疫机制提供新的见解，为干预一系列皮肤疾病提供新的治疗策略，包括感染性，免疫性和肿瘤性病因。候选人和环境：主要研究者是一名研究生研究员，接受过皮肤病学和免疫学的博士培训。他所接受的培训的广度允许这个提案的概念和综合，它跨越了先天免疫，传染病和皮肤生物学领域：候选人将在加州大学洛杉矶分校世界知名的免疫学家和皮肤科医生Robert Modlin的指导下。目标和职业发展：近期的目标是通过诱导不同的细胞因子应答来探讨皮肤中先天免疫细胞识别宿主DNA的机制。这将以麻风病为模型来完成，其结果对一系列皮肤病具有广泛的影响。长期目标是利用这些经验成为一名成熟的研究者，可以应用这些免疫学原理来获得洞察力并开发其他皮肤疾病的新疗法。相关性：皮肤中的先天免疫细胞识别DNA的能力是影响先天免疫应答的一种新的免疫机制，并且可以使用麻风作为模型来研究。对麻风病的研究有助于建立指导疾病治疗的免疫学范式，包括1型和2型T细胞免疫以及Toll样受体在微生物感染中的功能。通过本提案中的工作，我们将定义皮肤中先天免疫系统细胞识别DNA模式的机制，从而诱导有助于疾病发病机制的不同细胞因子反应。