Lung epithelial cell reprogramming by CD4 T cells

项目摘要 候选人信息：我是波士顿大学肺科约瑟夫·米兹格尔德博士实验室的博士后研究员。 中心自2018年1月以来，我的工作重点是阐明肺上皮细胞（LEC）和CD 4 T细胞 在肺炎球菌感染过程中， 肺炎我的职业目标是成为顶级学术机构的终身教职员工， 在学术阶梯的所有梯级（包括本科生，研究生和博士后）培养科学家， 研究不同细胞间相互作用对肺免疫和修复的机制和后果， 对各种感染、过敏、癌症和衰老的反应。为了确保我能及时地 为了实现我的职业目标，我制定了一个全面的计划，包括短期，中期， 以及长期的研究和训练目标。我已经召集了一个指导小组，将由博士。 Joseph Mizgerd（导师）和Darrell Kotton博士（共同导师）以及由Jose博士组成的咨询委员会 Ordovas-Montanes，Carla Kim博士和Ulrich von Andrian博士将确保我继续接受培训和进步 对肺上皮细胞和干细胞生物学，单细胞测序和计算生物学的精通， 和肺部免疫学沿着更大的赞赏癌症生物学和T细胞生物学。所有的 委员会成员将定期与我进行一对一的讨论和更大的委员会会议，以确保 我严格的研究和职业发展训练这将有助于我过渡到独立与独特的 这套技能使我能够成为健康和疾病期间LEC-CD 4 T细胞串扰领域的领导者。 拟议的研究和意义：反复吸入微生物建立肺部驻留记忆CD 4 T（TRM）细胞通过在再感染期间重塑LEC反应来赋予抗微生物免疫力。我们 初步数据显示，LEC和干细胞能够将抗原呈递给CD 4 T细胞， 肺炎，然后对他们过去与CD 4 T细胞的接触进行自主免疫记忆， 肺炎的解决。是否伴随抗原呈递给CD 4 T细胞的逆行信号传导 重新编程伴随和未来LEC功能未知。此外，存在，后生-和 转录组的程度，以及LEC免疫记忆对随后LEC功能的影响从未被证实。 被调查了因此，拟议的研究将确定是否参与免疫突触重塑LEC 在肺炎（K99）期间发挥作用，并将测试CD 4 T细胞是否在消退后的LEC中产生训练的免疫力 肺炎（R 00）拟议的目标将涉及使用单细胞测序技术，新的遗传学 工程小鼠模型和创新的谱系追踪策略，以测试CD 4 T细胞是否重新编程 LEC可以预防肺炎，对抗肺炎并从中恢复。研究结果将统一粘膜免疫领域，LEC 生物学和肺再生，并有可能确定LEC作为免疫调节靶点， 他们被训练来对抗感染和癌症，迅速修复肺部，并保持肺部的动态平衡。

PROJECT SUMMARY Candidate Information: I am a postdoctoral fellow in Dr. Joseph Mizgerd’s lab at Boston University Pulmonary Center since Jan-2018 and my work has focused on elucidating how lung epithelial cells (LECs) and CD4 T cells communicate with each other to optimize bacterial clearance and tissue resilience during pneumococcal pneumonia. My career objective is to become a tenure-track faculty member in a top-tiered academic institution, training scientists at all rungs of the academic ladder (including undergraduates, graduates, and postdocs) in investigating mechanisms- and consequences- of distinct cell-cell interactions on lung immunity and repair in response to diverse infections, allergies, cancer and aging. To ensure that I make timely progress towards achieving my career objectives, I have put together a comprehensive plan comprised of short-, intermediate- and long- term research and training goals. I have gathered a mentoring team that will be comprised of Dr. Joseph Mizgerd (Mentor) and Dr. Darrell Kotton (Co-mentor) and an advisory committee consisting of Dr. Jose Ordovas-Montanes, Dr. Carla Kim and Dr. Ulrich von Andrian that will ensure my continued training and progress towards proficiency in lung epithelial- and stem cell- biology, single cell sequencing and computational biology, and pulmonary immunology along with a larger appreciation of cancer biology and T cell biology. All the committee members will regularly meet me in one-on-one discussion and larger committee meetings to ensure my rigorous research and career development training. This will aid my transition to independence with a unique set of skills that empowers me to be a leader in the field of LEC-CD4 T cell crosstalk during health and disease. Proposed research and significance: Recurrent inhalation of microbes establishes lung-resident memory CD4 T (TRM) cells that confer anti-microbial immunity by remodeling LEC responses during reinfections. Our preliminary data shows that LECs and stem cells are capable of antigen presentation to CD4 T cells during pneumonia and then harboring autonomous immune memory of their past encounters with CD4 T cells post resolution of pneumonia. Whether retrograde signaling that accompanies antigen presentation to CD4 T cells reprograms concomitant and future LEC functions is unknown. Furthermore, the existence, epigenetic- and transcriptomic- extent, and consequences of LEC immune memory on subsequent LEC functions have never been investigated. Thus, the proposed studies will identify if engagement in an immune synapse remodels LEC functions during pneumonia (K99) and will test if CD4 T cells generate trained immunity in LECs post resolution of pneumonia (R00). The proposed aims will involve use of single cell sequencing technology, novel genetically engineered mouse models, and innovative lineage tracing strategies to test whether CD4 T cells reprogram LECs to preempt-, fight- and recover from- pneumonia. Findings will unify fields of mucosal immunity, LEC biology and lung regeneration and have the potential to identify LECs as immunomodulatory targets that can be trained to fight infections and cancers, promptly repair lungs, and to maintain pulmonary homeostasis.