Significance of Notch1 and Tribbles-2 in macrophage fusion and granuloma formatio

Notch1和Tribbles-2在巨噬细胞融合和肉芽肿形成中的意义

• 批准号: 7658674
• 负责人: Andras Schaffer
• 金额: $ 12.65万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7658674
• 关键词: Address; Adult; Advisory Committees; Biology; Bone remodeling; Cell fusion; Cells; Cellular Immunology; Chronic; Clinical; Clinical Pathology; Clinical Skills; Committee Members; Communicable Diseases; Data; Development; Disease; Elderly; Embryonic Development; Environment; Faculty; Gene Expression Profiling; Gene Expression Regulation; Gene Targeting; General Hospitals; Germ Cells; Giant Cell Granuloma; Giant Cells; Granuloma; Granulomatous; Hematopoietic stem cells; Homeostasis; Immune; Immune response; Immunocompromised Host; In Vitro; Incidence; Infection; Inflammatory; International; Laboratories; Lead; Life; Mammalian Cell; Massachusetts; Mediating; Medical center; Medicine; Mentors; Methods; Molecular; Mus; Muscle Fibers; Mycobacterium Infections; Myelogenous; Myeloid Leukemia; Organ; Pathology; Patients; Pear; Pennsylvania; Play; Postdoctoral Fellow; Prevalence; Principal Investigator; Program Development; Proteins; Regulation; Research; Research Personnel; Residencies; Role; Schistosomiasis; Scientist; Severities; Signal Transduction; Stem cells; Students; Training; Training Programs; Transgenic Mice; Tuberculosis; Universities; authority; career; cell type; design; follow-up; histiocyte; improved; in vivo; loss of function; macrophage; member; mycobacterial; notch protein; novel therapeutics; overexpression; professor; programs; research facility; skills; tissue regeneration; treatment strategy

DESCRIPTION (provided by applicant): This application describes a 5-year training program for the development of an academic career in Dermatopathology. The PI has completed formal residency training in Anatomical Pathology at the Massachusetts General Hospital and Anatomical Pathology and Clinical Pathology at the University of Pennsylvania. He is now expanding his clinical skills in Dermatopathology and scientific skills in Notch signaling. Dr. Warren Pear, an international authority in Notch biology, will mentor the principal investigator's scientific development. Dr. Pear is an Associate Professor of Pathology and Laboratory Medicine and has mentored numerous students, post-doctoral fellows, and junior faculty members. To further promote the investigator's scientific development, an Advisory Committee comprising highly regarded scientists including Drs. Ellen Pure, Sarah Millar and John Seykora had been established. Dr. Seykora will also mentor the principal investigator's clinical development. The proposed research focuses on the role of Notch and Trib2 in macrophages, a key cellular component of chronic infectious and inflammatory disorders such as tuberculosis and schistosomiasis. Depending on the organs afflicted and the immune status of the host, these disorders can be chronically debilitating or life-terminating, especially in immunocompromised patients. Therefore, understanding the mechanisms underlying macrophage differentiation and granuloma formation is of particular importance to medicine, and designing novel therapeutics to modulate macrophage-dependent immune responses is of critical value. To this end, this application specifically focuses on the role of Notch and its target gene Trib2 in the differentiation of macrophages to multinucleate giant cells, a critical cell type in granulomas. Given the Mentor's expertise regarding the Notch and Trib2 molecules, Dr. Pear's laboratory provides an ideal setting to study the precise roles played by these molecules in macrophage biology. Specific Aims include: 1) determining the significance of Notch 1 signaling in macrophage fusion ex vivo, 2) studying the significance of Notch 1 signaling in macrophage fusion in vivo and 3) examining the significance of Trib2 in macrophage fusion. In summary, macrophages play a major role in chronic inflammatory disorders ranging in severity from chronically debilitating to life-terminating infectious disorders, especially those in immune compromised patients. This application aims to dissect the molecular mechanisms involved in macrophage fusion. The intellectual strength and academic track-record of the principal investigator's Mentor and Advisory Committee members, the available expertise in methods required to study gene regulation and cellular immunology, as well as the quality of the research facilities at the University of Pennsylvania Medical Center comprise an ideal environment in which to conduct this proposed training program.

描述（由申请人提供）：本申请描述了一个为期5年的培训计划，在皮肤病理学的学术生涯的发展。PI已在马萨诸塞州总医院完成解剖病理学和宾夕法尼亚大学解剖病理学和临床病理学的正式住院医师培训。他现在正在扩展他在皮肤病理学方面的临床技能和Notch信号传导方面的科学技能。Warren Pear博士是Notch生物学的国际权威，他将指导首席研究员的科学发展。Pear博士是病理学和实验室医学的副教授，并指导了许多学生，博士后研究员和初级教师。为了进一步促进研究者的科学发展，成立了一个咨询委员会，成员包括Ellen Pure博士、Sarah Millar博士和John Seykora博士等德高望重的科学家。Seykora博士还将指导主要研究者的临床开发。这项研究的重点是Notch和Trib2在巨噬细胞中的作用，巨噬细胞是慢性感染性和炎症性疾病（如结核病和血吸虫病）的关键细胞成分。根据受影响的器官和宿主的免疫状态，这些疾病可能是慢性衰弱或生命终止，特别是在免疫功能低下的患者中。因此，了解巨噬细胞分化和肉芽肿形成的机制对医学特别重要，设计新的治疗方法来调节巨噬细胞依赖性免疫反应具有关键价值。为此，本申请特别关注Notch及其靶基因Trib2在巨噬细胞分化为多核巨细胞（肉芽肿中的关键细胞类型）中的作用。鉴于导师对Notch和Trib2分子的专业知识，Pear博士的实验室提供了一个理想的环境来研究这些分子在巨噬细胞生物学中发挥的确切作用。具体目标包括：1）测定Notch 1信号传导在离体巨噬细胞融合中的意义，2）研究Notch 1信号传导在体内巨噬细胞融合中的意义，和3）检查Trib2在巨噬细胞融合中的意义。总之，巨噬细胞在严重程度从慢性衰弱到终止生命的感染性疾病的慢性炎性疾病中起主要作用，特别是在免疫受损患者中。本申请旨在剖析参与巨噬细胞融合的分子机制。主要研究者的导师和咨询委员会成员的智力和学术记录，研究基因调控和细胞免疫学所需方法的现有专业知识，以及宾夕法尼亚大学医学中心研究设施的质量，构成了进行此拟议培训计划的理想环境。