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: 9902336
• 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 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9902336
• 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.

项目摘要 新型隐球菌是一种机会性真菌病原体，被吸入肺部， 扩散到大脑，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。尽管当代联合抗真菌药物 治疗，隐球菌病的存活率仅接近70%，并且高危人群正在扩大， 开发新的免疫抑制方案以治疗自身免疫和癌症。目前，蜂窝和 调节哺乳动物对C.新生儿的定义很模糊。 候选人香丽娜博士提出了一个职业发展培训计划， 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。她已经证明，炎症单核细胞发挥作用， 在宿主对C.通过促进真菌增殖和嗜酸性粒细胞 最终导致死亡本项目的目的是（1）评估C. 新型真菌破坏炎性单核细胞以促进真菌增殖，以及（2）评估如何 炎性单核细胞信号传导途径和细胞串扰破坏抗隐球菌免疫应答。 通过使用独特的小鼠模型和免疫学技术来操纵单核细胞特异性功能， 建议的研究将确定是否C.新生儿诱导炎性单核细胞分化为细胞 可以作为真菌传播的储存库，如果C.新生儿肺 嗜酸性粒细胞增多症是由炎性单核细胞通过信号适配器调节的病理过程 DAP 12和与嗜酸性粒细胞的细胞串扰。定义这些机制将加深我们对 调节肺对机会性真菌的免疫并为肺感染提供新机会的信号， 免疫调节干预对隐球菌病在脆弱的主机。 拟议的培训将在纪念斯隆凯特琳癌症中心举行，该机构 将来自不同科学和临床领域的专业知识融入综合研究环境。的 候选人将在顾问的指导下完成免疫学的教学和实践培训 该委员会由该领域的主要研究人员组成。鉴于她作为传染病医生的训练 和她的博士研究隐球菌毒力的调控机制的经验，候选人将开发 独特的技能使她能够从新的角度解决医学真菌学中长期存在的问题 以创造创新的解决方案。因此，在支持期结束时， 从事职业生涯作为一个独立的物理学家，科学家在真菌免疫学领域。