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

项目概要/摘要 该提案描述了一个为期五年的转化型职业发展指导培训计划 科学家研究皮肤病原体麻风分枝杆菌（mLEP）引起的机制 免疫抑制性骨髓源性抑制细胞 (MDSC) 和 M2 巨噬细胞 (M) 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 麻风病（L-lep）患者。我们将 L-lep 患者的 MDSC 与所见的类似细胞进行比较 自限性或结核病 (T-lep) 形式的疾病。我们已确定 IL-34 是一个潜在因素 导致免疫抑制性骨髓细胞的产生。该项目解决了以下几个目标 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）有助于皮肤感染期间的免疫耐受，2) 评估如何 MDSC 和 M2 M 影响麻风病的免疫反应（例如 T 细胞反应）。我完成了博士学位研究 对与狼疮自身抗原相关的自身 RNA 产生先天免疫反应，并具有 完成两项博士后研究金。我的第一个奖学金研究了骨髓细胞的重要性 小鼠脓毒症中的发育和 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 IL-10 产生的影响。通过这个提案，我将开发新的分子技术， 包括高通量 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。我还将通过以下方式扩展我的临床转化技能 通过与健康对照者和麻风病患者的定期会议进行实验 临床医生和转化研究课程。这些新技术和技能可以虚拟地应用到 任何皮肤病。这一关键的指导培训阶段将在罗伯特的指导下进行 莫德林医学博士是转化皮肤免疫学研究的先驱，他培养了许多 独立调查员。莫德林博士将帮助指导我完成成为一名 独立研究员。本文提出的研究将增进对新型骨髓细胞如何 细胞发育并有助于皮肤对感染的免疫耐受。这个计划将使我能够发展 开展本研究项目以及未来研究项目所需的所有技能和工具，以及 一位成功导师的指导能够帮助我成为一名成功的独立人士 调查员。

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.