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

项目概要/摘要 该补充文件将在达拉·丰塞卡·巴拉达雷斯 (Dara Fonseca Balladares) 女士完成她的学业后为她提供一年的支持 学士学位，以帮助她实现就读医学院的医学博士-博士课程的职业目标，以及 成为一名独立的医师科学家。该研究奖学金将为 Fonseca Balladares 女士提供 进行实验的技术能力；计划实验、解释结果和适当计划的认知能力 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，以及她未来的医学职业生涯）。 Fonseca Balladares 女士将完成详细的计划 提案中概述的渐进里程碑，包括获得实验技术和制定 新颖的假设。她将参加加州大学的多个职业发展项目 伯克利和旧金山，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 Graham 和预先确定的职业发展咨询委员会合作， 她将监督她的实验研究计划和职业发展培训的过程。预计 Fonseca Balladares 女士将在 ATS 国际会议上展示她的工作，并出版第一作者的作品 论文报告了她在完成拟议研究时获得的发现。 Dara Fonseca Balladares 女士的研究项目将调查 CD4 T 细胞在血吸虫病诱发的肺动脉高压 (PH) 中的作用。我们使用的鼠标模型采用 在用血吸虫卵进行静脉内 (IV) 攻击之前进行腹膜内 (IP) 致敏以引起 PH，我们 已表明 Th2 CD4 T 细胞对于血吸虫诱导的 PH 是必要且充分的，可指导 2 型 炎症导致表达血小板反应蛋白-1 (TSP-1) 的 Ly6c 单核细胞募集，从而导致 TGF-β 激活可诱导血管细胞出现病理表型。初步的初步实验 表明肺部存在活化的 CD4 T 细胞，不需要从淋巴结迁移到 引发炎症诱发的 PH，因为 FTY720 可以阻止淋巴结中的 T 细胞，但不能阻断 PH 表型。因此，补充假设是肺部中预先准备好的 T 细胞就足够了 通过 IV 卵激发诱导 2 型免疫驱动的血吸虫 PH。补充文件的具体目标 1 将 描述 IP 致敏后淋巴结和肺组织中 CD4 T 细胞的数量和表型 和静脉输卵挑战。补充剂的具体目标 2 将确定肺部是否已存在 CD4 T 细胞 足以诱导 2 型免疫和血吸虫诱导的 PH。总体而言，该主题属于 母基金，旨在确定必要的树突状细胞和 CD4 T 细胞的功能 对于 Schistosoma-PH，现在正在寻求确定 CD4 T 细胞的具体位置要求。

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.