Inflammatory monocytes and host control of cryptococcosis

炎症单核细胞和隐球菌病的宿主控制

• 批准号: 10097959
• 负责人: Lena J Heung
• 金额: $ 16.59万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-16 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10097959
• 关键词: Ablation; Acquired Immunodeficiency Syndrome; Acute; Adaptor Signaling Protein; Adoptive Transfer; Advisory Committees; Antifungal Therapy; Autoimmunity; Bone Marrow; Brain; Cells; Cessation of life; Chimera organism; Clinical; Communicable Diseases; Cryptococcosis; Cryptococcus; Cryptococcus neoformans; Cryptococcus neoformans infection; Defect; Development; Disease Progression; Dissection; Doctor of Philosophy; Environment; Generations; Genes; Growth; Immune; Immune response; Immune system; Immunity; Immunocompromised Host; Immunologic Techniques; Immunologics; Immunology; Individual; Infection; Inflammatory; Inflammatory Response; Inhalation; Institution; Interleukin-5; Intervention; Knowledge; Lead; Life; Link; Lung; Malignant Neoplasms; Mediating; Medical; Memorial Sloan-Kettering Cancer Center; Meningoencephalitis; Modeling; Molecular; Mus; Organ Transplantation; Outcome; Pathologic Processes; Pathway interactions; Patients; Pattern; Physicians; Play; Populations at Risk; Pulmonary Eosinophilia; Regimen; Regulation; Research; Research Personnel; Role; Scientist; Signal Pathway; Signal Transduction; Solid; Survival Rate; TYROBP gene; Technical Expertise; Testing; The science of Mycology; Training; Training Programs; Transgenic Organisms; Virulence; Work; beta-Chemokines; career; career development; design; eosinophil; experience; fungus; immunoregulation; improved; in vivo; innovation; monocyte; mouse model; novel; pathogenic fungus; recruit; respiratory; skills; therapy development

Project Summary Cryptococcus neoformans is an opportunistic fungal pathogen that is inhaled into the lungs and can disseminate to the brain, causing a highly fatal meningoencephalitis in immunocompromised patients, particularly those with AIDS, solid organ transplants, and cancer. Despite contemporary combination antifungal therapy, the survival rate for cryptococcosis approaches only 70%, and the at-risk population is expanding with the development of new immunosuppressive regimens for autoimmunity and cancer. Currently, the cellular and molecular mechanisms that regulate the mammalian immune response to C. neoformans are poorly defined. The candidate, Dr. Lena J. Heung, proposes a career development training program that will give her the knowledge and technical skills necessary to investigate the immune mechanisms of inflammatory monocytes in a murine model of pulmonary cryptococcosis. She has demonstrated that inflammatory monocytes play a detrimental role during the host response to C. neoformans by promoting fungal proliferation and eosinophil recruitment in the lung that ultimately lead to death. The aims of the project are to (1) evaluate how C. neoformans subverts inflammatory monocytes to promote fungal proliferation and (2) evaluate how inflammatory monocyte signaling pathways and cellular crosstalk disrupt anti-cryptoccocal immune responses. By using unique murine models and immunologic techniques to manipulate monocyte-specific functions, the proposed studies will determine if C. neoformans induces inflammatory monocytes to differentiate into cells that can be exploited as fungal reservoirs for dissemination and if C. neoformans-induced pulmonary eosinophilia is a pathologic process regulated by inflammatory monocytes through the signaling adapter DAP12 and cellular crosstalk with eosinophils. Defining these mechanisms will deepen our understanding of the signals that regulate pulmonary immunity to opportunistic fungi and inform novel opportunities for immunomodulatory interventions against cryptococcosis in vulnerable hosts. The proposed training will take place at Memorial Sloan Kettering Cancer Center, an institution that incorporates expertise from diverse scientific and clinical fields into an integrated research environment. The candidate will complete didactic and practical bench training in immunology with the guidance of an advisory committee composed of leading researchers in the field. Given her training as an Infectious Diseases physician and her PhD experience studying regulatory mechanisms of cryptococcal virulence, the candidate will develop a unique skill set that will enable her to tackle long-standing problems in medical mycology from a new perspective in order to create innovate solutions. Thus, at the end of the period of support, she will be poised to undertake a career as an independent physician-scientist in the field of fungal immunology.

项目概要 新型隐球菌是一种机会性真菌病原体，被吸入肺部并可 传播到大脑，在免疫功能低下的患者中引起高度致命的脑膜脑炎， 特别是那些患有艾滋病、实体器官移植和癌症的人。尽管现代组合抗真菌药物 治疗后，隐球菌病的存活率仅接近 70%，且高危人群正在不断扩大 开发针对自身免疫和癌症的新免疫抑制疗法。目前，蜂窝和 调节哺乳动物对新型隐球菌免疫反应的分子机制尚不清楚。 候选人 Lena J. Heung 博士提出了一项职业发展培训计划，该计划将使她能够 研究炎症单核细胞免疫机制所需的知识和技术技能 肺隐球菌病的小鼠模型。她证明炎症单核细胞发挥着 通过促进真菌增殖和嗜酸性粒细胞，在宿主对新型隐球菌的反应中发挥有害作用 肺部的募集最终导致死亡。该项目的目标是 (1) 评估 C. 新型隐球菌破坏炎症单核细胞以促进真菌增殖，并且（2）评估如何 炎症单核细胞信号通路和细胞串扰会破坏抗隐球菌免疫反应。 通过使用独特的小鼠模型和免疫技术来操纵单核细胞特异性功能， 拟议的研究将确定新型隐球菌是否诱导炎症单核细胞分化为细胞 可以用作传播的真菌储存库，并且如果新型隐球菌诱导的肺 嗜酸性粒细胞增多是炎症单核细胞通过信号适配器调节的病理过程 DAP12 和细胞与嗜酸性粒细胞的串扰。定义这些机制将加深我们对 调节肺部对机会性真菌的免疫并为感染提供新机会的信号 针对脆弱宿主隐球菌病的免疫调节干预措施。 拟议的培训将在纪念斯隆凯特琳癌症中心进行，该机构 将不同科学和临床领域的专业知识融入到综合研究环境中。这 候选人将在顾问的指导下完成免疫学的教学和实践台架培训 委员会由该领域的顶尖研究人员组成。鉴于她接受过传染病医生的培训 以及她研究隐球菌毒力调节机制的博士学位经验，候选人将发展 一套独特的技能将使她能够从新的角度解决医学真菌学中长期存在的问题 的观点，以创建创新的解决方案。因此，在支持期结束时，她将做好准备 作为真菌免疫学领域的独立医师科学家开展职业生涯。