IL-34 regulation of cutaneous immunity by polarizing myeloid cell differentiation

IL-34 通过极化骨髓细胞分化调节皮肤免疫

• 批准号: 10402636
• 负责人: Kindra Kelly-Scumpia
• 金额: $ 12.21万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10402636
• 关键词: Address; Affect; Bacteria; Blood; CD14 gene; CD34 gene; Cell Communication; Cell Differentiation process; Cell physiology; Cells; Characteristics; Chronic; Clinical; Confocal Microscopy; Cutaneous; Data; Development; Disease; Doctor of Philosophy; Failure; Fellowship; Frequencies; Functional disorder; Generations; Goals; Growth; HLA-DR Antigens; High-Throughput RNA Sequencing; Host Defense; Host Defense Mechanism; Human; Immune; Immune Tolerance; Immune response; Immunity; Immunology; Immunosuppression; Impairment; In Situ; In Vitro; Infection; Infection Control; Infectious Skin Diseases; Inflammatory; Innate Immune Response; Interferon Type I; Interleukin-10; Interleukins; Investigation; Knowledge; Ku70 protein; L Cells; Lead; Lepromatous Leprosy; Leprosy; Lesion; Ligands; Mentors; Mentorship; Modeling; Molecular; Mus; Mycobacterium leprae; Myelogenous; Myeloid Cells; Myeloid Progenitor Cells; Myeloid-derived suppressor cells; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Pathology; Pathway interactions; Patients; Peptides; Phase; Phenotype; Play; Population; Production; Public Health; RNA; Regulation; Research; Research Personnel; Research Project Grants; Role; Sepsis; Site; Skin; Source; Stromal Cells; System; T cell response; T-Lymphocyte; Techniques; Testing; Therapeutic; Tissues; Training; Training Programs; Transcriptional Regulation; Translational Research; Work; adaptive immune response; base; career development; chronic infection; combat; endoplasmic reticulum stress; experimental study; human model; immunoregulation; improved; macrophage; meetings; monocyte; myeloid cell development; novel; novel therapeutics; pathogen; prevent; progenitor; programs; response; skills; skin disorder; skin lesion; stem cells; tool; translational model; translational scientist; virtual

PROJECT SUMMARY/ABSTRACT This proposal describes a five-year mentored training program for the career development of a translational scientist to examine the mechanism by which a cutaneous pathogen, mycobacterium leprae (mLEP), causes the expansion of immunosuppressive myeloid derived suppressor cells (MDSC) and M2 macrophages (M) that produce interleukin (IL)-10, a factor critical for failure of host defense and pathogen persistence in lepromatous leprosy (L-lep) patients. We will compare the MDSC from L-lep patients with the similar cells seen in the self-limiting or tuberculoid (T-lep) form of disease. We have identified IL-34 as a potential factor that leads to the production of the immunosuppressive myeloid cells. This project addresses several goals of NIAMS using leprosy as a translational model to study mechanisms that impact cutaneous immunity, including: 1) identifying how induction of IL-34 can lead to the production of immunosuppressive myeloid populations (MDSC and M2 M) that contribute to immune tolerance during cutaneous infection and 2) evaluating how MDSC and M2 M affect immune responses in leprosy (eg. T cell responses). I completed a PhD investigating the generation of innate immune responses to self-RNAs associated with lupus autoantigens, and have completed two postdoctoral fellowships. My first fellowship examined the importance of myeloid cell development and type I interferon responses in murine sepsis. My second fellowship studied the contribution of type I interferon to IL-10 production in leprosy. Through this proposal, I will develop new molecular techniques, including high throughput RNA sequencing with the computational analytical skills required to understand transcriptional regulation, as well as confocal microscopy. I will also expand my clinical translational skills, by performing experiments involving skin from healthy controls and leprosy patients, by regular meetings with clinicians and coursework in translational research. These new techniques and skills can be applied to virtually any skin disorder. This critical mentored phase of training will be performed under the mentorship of Robert Modlin, MD, a pioneer in translational cutaneous immunology research, who has trained a number of independent investigators. Dr. Modlin will help to guide me through the necessary steps to becoming an independent researcher. The research proposed herein will improve the understanding of how novel myeloid cells develop and contribute to cutaneous immune tolerance to infection. This program will allow me to develop all of the skills and tools needed to embark upon this research project as well as future research projects, with the guidance of a successful mentor capable of assisting me into becoming a successful independent investigator.

项目总结/摘要 该提案描述了一个为期五年的指导培训计划，用于翻译的职业发展 科学家研究皮肤病原体麻风分枝杆菌（mLEP）引起 免疫抑制性髓源性抑制细胞（MDSC）和M2巨噬细胞（M2）的扩增 产生白细胞介素（IL）-10，这是宿主防御失败和病原体持续存在的关键因素， 瘤型麻风（L-lep）患者。我们将比较L-lep患者的MDSC与所见的类似细胞 自限性或类结核病（T-lep）。我们已经确定IL-34是一个潜在的因素， 导致免疫抑制性骨髓细胞的产生。该项目涉及以下几个目标： NIAMS使用麻风病作为转化模型来研究影响皮肤免疫的机制，包括： 1)确定IL-34的诱导如何导致免疫抑制性骨髓细胞群的产生 (MDSC和M2 M β），其有助于皮肤感染期间的免疫耐受，以及2）评估如何 MDSC和M2 M β影响麻风的免疫应答（例如，T细胞应答）。我完成了一个博士研究 对狼疮自身抗原相关的自身RNA的先天免疫应答的产生， 完成了两个博士后奖学金。我的第一个研究项目是研究骨髓细胞 发展和I型干扰素的反应在鼠败血症。我的第二个奖学金研究了 Ⅰ型干扰素对麻风患者IL-10产生的影响通过这个提议，我将开发新的分子技术， 包括高通量RNA测序与所需的计算分析技能， 转录调控，以及共聚焦显微镜。我还将扩大我的临床翻译技能， 进行实验，涉及皮肤从健康控制和麻风病人，定期会议， 临床医生和转化研究课程。这些新技术和技能可以应用于虚拟 任何皮肤病。这一关键的培训指导阶段将在罗伯特· Modlin博士是皮肤免疫学研究的先驱，他已经培养了许多 独立调查员。莫德林博士将帮助指导我通过必要的步骤，成为一个 独立研究员。本文提出的研究将提高对新的髓样细胞如何在骨髓中表达的理解。 细胞发育并有助于皮肤对感染的免疫耐受。这个程序将允许我开发 所有的技能和工具，需要着手这个研究项目以及未来的研究项目， 一个成功的导师的指导，能够帮助我成为一个成功的独立 调查员