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

项目摘要/摘要 本提案描述了一项为期五年的指导培训计划，旨在促进翻译人员的职业发展 科学家研究一种皮肤病原体麻风分枝杆菌(MLEP)引起的机制 免疫抑制髓系抑制细胞和M_2巨噬细胞(M-)的扩增 产生白介素10，白介素10是导致宿主防御失败和病原菌持续存在的关键因素 麻风(L-LEP)患者。我们将L-LEP患者的骨髓间充质干细胞与类似的细胞进行比较。 在自限性或类结核(T-LEP)型疾病中。我们已经确定IL-34是一个潜在的因素 导致免疫抑制髓系细胞的产生。该项目解决了以下几个目标 NIAMS使用麻风病作为翻译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髓系细胞的产生 (MDSC和M2 M)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影响麻风患者的免疫反应(例如。T细胞反应)。我完成了博士学位的调查 产生对与狼疮自身抗原相关的自身RNA的先天免疫反应，并具有 完成了两个博士后奖学金。我的第一个研究员研究了髓系细胞的重要性。 小鼠脓毒症的发生和I型干扰素反应。我的第二个研究员研究了 麻风I型干扰素对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，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。我还将扩展我的临床翻译技能，通过 对健康对照和麻风患者的皮肤进行实验，定期与 临床医生和翻译研究的课程工作。这些新的技术和技能可以应用于虚拟 任何皮肤病。这一关键的指导阶段的培训将在罗伯特的指导下进行 莫德林，医学博士，翻译皮肤免疫学研究的先驱，他培训了许多 独立调查人员。莫德林博士将帮助我完成成为一名 独立研究人员。本文提出的研究将提高对新髓系如何 细胞的发展有助于皮肤对感染的免疫耐受。这个项目将使我能够发展 开展这一研究项目以及未来研究项目所需的所有技能和工具， 一位成功的导师的指导，能够帮助我成为一个成功的独立人士 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.