Lung epithelial cell reprogramming by CD4 T cells

CD4 T 细胞对肺上皮细胞进行重编程

• 批准号: 10371548
• 负责人: Anukul T Shenoy
• 金额: $ 13.53万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10371548
• 关键词: Address; Adoptive Transfer; Advisory Committees; Aging; Antigen Presentation; Antigen-Presenting Cells; Asthma; Boston; CD4 Positive T Lymphocytes; Cancer Biology; Cell Communication; Cell physiology; Cells; Cellular biology; Clinical; Committee Members; Communication; Communities; Computational Biology; Data; Data Set; Disease; Ensure; Epigenetic Process; Epithelial Cells; Etiology; Faculty; Future; GTP-Binding Protein alpha Subunits, Gs; Genetic Transcription; Genetically Engineered Mouse; Goals; Grant; Health; High-Throughput Nucleotide Sequencing; Homeostasis; Human; Hypersensitivity; Immune; Immunity; Immunologic Memory; Immunology; Infection; Inhalation; Injury; Institution; Instruction; Interferon Type II; Lung; Malignant Neoplasms; Memory; Mentors; Microbe; Mucosal Immunity; Mucous Membrane; Mus; Myeloid Cells; Neutrophil Infiltration; PD-1/PD-L1; Patients; Phenocopy; Pneumococcal Pneumonia; Pneumonia; Postdoctoral Fellow; Recombinants; Recurrence; Reporting; Research; Research Training; Resolution; Role; Scientist; Signal Transduction; Streptococcus pneumoniae; T-Lymphocyte; Technology; Testing; Time; Tissues; Training; Universities; Work; antigen test; antimicrobial; career; career development; cell regeneration; cytokine; epigenome; epithelial stem cell; experience; experimental study; fighting; immune checkpoint blockade; immunological synapse; immunoregulation; imprint; in vivo; injury and repair; innovation; interest; lung regeneration; lung repair; meetings; member; memory recall; microbial; mouse model; novel; preempt; programmed cell death ligand 1; recruit; regenerative; repaired; research and development; resilience; response; single cell sequencing; single-cell RNA sequencing; skills; stem cell biology; stem cell proliferation; stem cells; tenure track; tool; transcription factor; transcriptomics; undergraduate student

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.

项目摘要 候选人信息：我是波士顿大学肺部约瑟夫·米兹格德（Joseph Mizgerd）实验室的博士后研究员 自2018年1月以来的中心，我的工作重点是阐明肺上皮细胞（LEC）和CD4 T细胞如何 相互沟通以优化肺炎肺炎期间细菌清除率和组织弹性 肺炎。我的职业目标是成为一名顶级学术机构的终身教师， 在学术阶梯的所有阶段（包括本科生，毕业生和博士后）的培训科学家 研究对肺免疫和修复的不同细胞 - 细胞相互作用的机制和后果 对潜水员感染，过敏，癌症和衰老的反应。确保我及时进步 实现我的职业目标，我汇总了一项全面的计划，完成了简短的中级， 以及长期的研究和培训目标。我聚集了一支将完成博士的心理团队。 约瑟夫·米兹格（Joseph Mizgerd）（导师）和达雷尔·科顿（Darrell Kotton）博士（同事）以及由何塞（Jose）博士组成的咨询委员会 Ordovas-Montanes，Carla Kim博士和Ulrich von Andrian博士将确保我继续培训和进步 熟练肺上皮和干细胞生物学，单细胞测序和计算生物学， 和肺免疫学以及对癌症生物学和T细胞生物学的更大欣赏。全部 委员会成员将定期在一对一的讨论和更大的委员会会议上与我见面，以确保 我严格的研究和职业发展培训。这将有助于我以独特的方式过渡到独立 在健康和疾病期间，一系列技能使我成为LEC-CD4 T细胞串扰领域的领导者。 拟议的研究和意义：微生物重复吸入建立的肺居民记忆CD4 t（TRM）细胞通过重塑在恢复过程中通过重塑LEC反应来接触抗微生物免疫。我们的 初步数据表明，LEC和干细胞能够在CD4 T细胞中抗原呈递 肺炎，然后怀有对过去与CD4 T细胞相遇的自主免疫记忆 肺炎的分辨率。是否涉及抗原表现为CD4 T细胞的逆行信号传导是否 重编程伴随和未来的LEC功能尚不清楚。此外，存在，表观遗传和 LEC免疫记忆对随后的LEC功能的转录范围和后果从未 我们接受了调查。这是拟议的研究将确定参与免疫突触是否重塑了LEC 肺炎期间的功能（K99），将测试CD4 T细胞是否在分辨率后LEC中产生训练有素的免疫支持 肺炎（R00）。提出的目的将涉及使用单细胞测序技术，从遗传上进行新颖 工程的鼠标模型以及创新的谱系跟踪策略，以测试CD4 T细胞是否重新编程 从肺炎中抢先，战斗和恢复的lecs。调查结果将统一粘膜免疫的领域，LEC 生物学和肺部再生，并有可能将LEC鉴定为可以是免疫调节靶标的 经过培训，可以与感染和癌症作斗争，迅速修复肺部并维持肺稳态。