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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要/摘要该提案描述了一项为期五年的培训计划，以进行翻译的职业发展科学家检查皮肤病原体（MLEP）的皮肤病原体（MLEP）的机制免疫抑制髓样衍生的抑制细胞（MDSC）和M2巨噬细胞（M）的扩展产生白介素（IL）-10，这是宿主防御失败和病原体持久性失败的因素麻风病（L-LEP）患者。我们将比较来自L-LEP患者的MDSC 以疾病的自限或结核（T-Lep）形式。我们已经确定IL-34是一个潜在的因素导致免疫抑制性髓样细胞的产生。该项目解决了几个目标 NIAMS使用麻风病作为翻译模型来研究影响皮肤免疫学的机制，包括： 1）确定IL-34的诱导如何导致免疫抑制髓样群的产生（MDSC和M2M）在皮肤感染过程中有助于免疫耐受性，2）评估如何 MDSC和M2M会影响麻风病中的免疫复杂（例如T细胞反应）。我完成了博士调查对与狼疮自动抗原相关的自发反应的先天免疫反应产生，并具有完成了两项博士后研究金。我的第一个研究金检查了髓样细胞的重要性鼠类败血症中的开发和I型干扰素反应。我的第二个奖学金研究了 I型干扰素对麻风病中的IL-10产生。通过此建议，我将开发新的分子技术，包括高吞吐量RNA测序以及理解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通过定期会议与转化研究的临床医生和课程。这些新技术和技能可以实际上应用于任何皮肤疾病。这一严重修补的培训阶段将在罗伯特的遗嘱下进行 Modlin，医学博士，翻译皮肤免疫学研究的先驱，他培训了许多独立调查员。 Modlin博士将帮助我完成必要的步骤，成为一个独立研究员。本文提出的研究将提高人们对新型髓样的理解细胞发展并有助于皮肤免疫耐受性感染。这个程序将使我得以发展启动该研究项目以及未来的研究项目所需的所有技能和工具以及成功的心理能够帮助我成为成功独立的指导研究者。