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

基本信息

批准号：
7880714
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
项目类别：
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/7880714
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 Dermatopathology 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

项目摘要

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）：本申请描述了一项为期5年的培训计划，以开发皮肤病理学的学术生涯。 PI已在马萨诸塞州综合医院和宾夕法尼亚大学的解剖病理学和临床病理学上完成了解剖病理学的正式居住培训。现在，他正在扩大自己的临床技能，方面的凹槽信号和科学技能。 Notch生物学的国际权威沃伦·皮尔（Warren Pear）博士将指导主要研究者的科学发展。 Pear博士是病理学和实验室医学副教授，曾指导众多学生，博士后研究员和初级教职员工。为了进一步促进研究者的科学发展，一个咨询委员会由包括Drs在内的备受推崇的科学家组成。 Ellen Pure，Sarah Millar和John Seykora已成立。 Seykora博士还将指导主要研究者的临床发展。拟议的研究重点是Notch和Trib2在巨噬细胞中的作用，巨噬细胞是慢性传染和炎症性疾病（如结核病和血吸虫病）的关键细胞成分。根据遭受宿主的器官和免疫状态，这些疾病可能长期使人衰弱或生命终止，尤其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的基础机制对于医学尤其重要，并且设计新型的治疗剂以调节巨噬细胞依赖性免疫反应是至关重要的。为此，该应用专门侧重于Notch及其靶基因Trib2在巨噬细胞分化对多核细胞的分化中的作用，该细胞是颗粒中的关键细胞类型。鉴于导师在Notch和Trib2分子方面的专业知识，Pear's Laboratory提供了一个理想的环境，以研究这些分子在巨噬细胞生物学中扮演的精确作用。具体目的包括：1）确定Notch 1信号在巨噬细胞融合中的重要性，2）研究Notch 1信号在体内巨噬细胞融合中的重要性和3）检查Trib2在巨噬细胞融合中的重要性。总而言之，巨噬细胞在慢性炎症性疾病中起着重要作用，从慢性衰弱到生命终止感染疾病，尤其是患者的严重性。该应用旨在剖析与巨噬细胞融合有关的分子机制。首席研究员的导师和咨询委员会成员的智力实力和学术轨道唱片《研究基因调节和细胞免疫学所需的方法的可用专业知识》，以及宾夕法尼亚大学医学中心研究设施的质量，包括一个理想的环境，其中有一个理想的环境。