Determining the location and phenotype requirement of CD4 T cells in schistosomiasis pulmonary hypertension

确定血吸虫病肺动脉高压中 CD4 T 细胞的位置和表型要求

• 批准号: 10732723
• 负责人: Brian Barkley Graham
• 金额: $ 5.49万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10732723
• 关键词: Adopted; Advisory Committees; Award; Blood Vessels; CD4 Positive T Lymphocytes; California; Cells; Clinical; Dedications; Dendritic Cells; Doctor of Philosophy; Education; Educational process of instructing; Ethics; Feedback; Fellowship; Formulation; Funding; Future; Goals; Immune; Immunity; Immunology; Inflammation; Inflammatory; International; Intravenous; Knowledge; Location; Lung; Mediastinal lymph node group; Medicine; Mentors; Monitor; Paper; Pathologic; Phenotype; Physicians; Positioning Attribute; Program Development; Publishing; Pulmonary Hypertension; Reporting; Research; Research Personnel; Research Project Grants; San Francisco; Schistosoma; Schistosomiasis; Scientist; Structure of parenchyma of lung; T-Lymphocyte; Technical Expertise; Techniques; Thrombospondin 1; Time; Training; Transforming Growth Factor beta; Universities; Work; career; career development; cell motility; cognitive skill; egg; experimental study; inhibitor; instructor; intraperitoneal; knowledge base; lymph nodes; matriculation; medical schools; migration; monocyte; mouse model; novel; parent grant; prevent; programs; recruit; responsible research conduct; symposium

PROJECT SUMMARY / ABSTRACT This Supplement will support Ms. Dara Fonseca Balladares for 1 year following completion of her baccalaureate to help her achieve her career goals of attending medical school in an MD-PhD program, and becoming an independent physician scientist. This research fellowship will provide Ms. Fonseca Balladares with technical skills to perform experiments; cognitive skills to plan experiments, interpret results and plan appropriate next steps; and additional education in research including ethics and immunology (relevant to this research project now, and her future career in medicine). Ms. Fonseca Balladares will complete a detailed plan of progressive milestones outlined in the proposal, including acquiring experimental techniques and formulation of novel hypotheses. She will participate in several career development programs at the University of California Berkeley and San Francisco, including formal coursework in topics relevant to the research project and her career goals. She will work with the PI Graham and a pre-identified career development advisory committee, who will monitor the course of her experimental research plan and career development training. It is expected that Ms. Fonseca Balladares will present her work at the ATS international conference, and publish a first author paper reporting her findings obtained in completing the proposed research. Ms. Dara Fonseca Balladares’ research project will investigate the phenotype and location requirement of CD4 T cells in schistosomiasis-induced pulmonary hypertension (PH). The mouse model we use employs intraperitoneal (IP) sensitization prior to intravenous (IV) challenge with Schistosoma eggs to cause PH, and we have shown Th2 CD4 T cells are necessary and sufficient for Schistosoma-induced PH, which direct Type 2 inflammation that causes recruitment of Ly6c+ monocytes which express thrombospondin-1 (TSP-1), resulting in TGF-β activation which induces pathologic phenotypes in the vascular cells. An initial preliminary experiment suggested that there are activated CD4 T cells in the lungs which do not require migration from lymph nodes to trigger inflammation-induced PH, as FTY720 which arrests T cells in lymph nodes did not block the PH phenotype. The supplement hypothesis is thus that primed and pre-positioned T cells in the lung are sufficient to induce Type 2 immune-driven Schistosoma PH with IV egg challenge. Specific Aim 1 of the supplement will describe the numbers and phenotype of CD4 T cells in lymph nodes and lung tissue following IP sensitization and IV egg challenge. Specific aim 2 of the supplement will determine if CD4 T cells already present in the lungs are sufficient to induce Type 2 immunity and Schistosoma-induced PH. Overall this topic is within the scope of the parent grant, which seeks to determine the functions of dendritic cells and CD4 T cells which are necessary for Schistosoma-PH, by now seeking to identify the specific location requirement of CD4 T cells.

项目总结/摘要 本补编将在达拉·丰塞卡·巴拉达雷斯女士完成其任期后的一年内提供支助。 学士学位，以帮助她实现她的职业目标，参加医学院的MD-PhD课程， 成为一名独立的医学科学家。这项研究金将为丰塞卡·巴拉达雷斯女士提供 进行实验的技术技能;计划实验，解释结果和计划适当的认知技能 下一步;以及包括伦理学和免疫学在内的研究方面的额外教育（与本研究相关 现在的项目，以及她未来的医学生涯）。丰塞卡·巴利亚达雷斯女士将完成一项详细的计划， 提案中概述的进展里程碑，包括获得实验技术和制定 新的假设。她将参加加州大学的几个职业发展项目 伯克利和弗朗西斯科，包括与研究项目和她相关的主题的正式课程作业 职业目标。她将与PI格雷厄姆和预先确定的职业发展咨询委员会， 她将监督她的实验研究计划和职业发展培训的进程。预计 Fonseca Balladares女士将在ATS国际会议上介绍她的工作，并出版第一作者 报告她在完成拟议的研究中获得的发现的论文。 达拉·丰塞卡·巴拉达雷斯女士的研究项目将调查 CD 4 T细胞在肺孢子虫病诱导的肺动脉高压（PH）中的作用我们使用的小鼠模型 腹腔内（IP）致敏，然后静脉内（IV）挑战血吸虫卵引起PH，我们 已经表明Th 2 CD 4 T细胞对于血吸虫诱导的PH是必要的和足够的，其直接导致2型 引起表达血小板反应蛋白-1（TSP-1）的Ly 6c+单核细胞募集的炎症，导致 TGF-β活化，其诱导血管细胞中的病理表型。最初的初步实验 提示在肺中存在活化的CD 4 T细胞，其不需要从淋巴结迁移至 触发炎症诱导的PH，因为FTY 720在淋巴结中抑制T细胞并不阻断PH 表型因此，补充假说认为，肺中的致敏和预先定位的T细胞是足够的 用IV卵攻击诱导2型免疫驱动的血吸虫PH。补充的具体目标1将 描述IP致敏后淋巴结和肺组织中CD 4 T细胞的数量和表型 和IV鸡蛋挑战。补充剂的具体目标2将确定CD 4 T细胞是否已经存在于肺部 足以诱导2型免疫和血吸虫诱导的PH。总体而言，本主题属于 父母补助金，旨在确定树突细胞和CD 4 T细胞的功能，这是必要的 对于血吸虫-PH，现在寻求确定CD 4 T细胞的特定位置要求。