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.

项目总结 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 自2018年1月至今，我的工作重点是阐明肺上皮细胞(LECs)和CD4T细胞 肺炎球菌肺炎期间相互沟通以优化细菌清除和组织弹性 肺炎。我的职业目标是成为一流学术机构的终身教职员工， 培训所有学术阶梯的科学家(包括本科生、研究生和博士后) 研究不同细胞-细胞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。以确保我及时取得进展 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、中期和 以及长期的研究和培训目标。我已经召集了一个指导团队，这个团队将由Dr。 约瑟夫·米兹格德(导师)和达雷尔·科顿博士(共同导师)以及由何塞博士组成的咨询委员会 奥多瓦斯-蒙大拿，卡拉·金博士和乌尔里希·冯·安德里安博士，这将确保我继续训练和进步 精通肺上皮细胞和干细胞生物学、单细胞测序和计算生物学， 以及肺部免疫学，以及对癌症生物学和T细胞生物学的更大了解。所有的 委员会成员将定期在一对一的讨论和较大的委员会会议上与我会面，以确保 我严谨的研究和职业发展培训。这将有助于我向独立的过渡，这是一个独特的 这些技能使我在健康和疾病期间成为LEC-CD4T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的记忆CD4 T(TRM)细胞，在再次感染期间通过重塑LEC反应来提供抗微生物免疫。我们的 初步数据显示，晶状体上皮细胞和干细胞能够在 肺炎，然后拥有自主免疫记忆的他们过去遇到的CD4T细胞后 肺炎的消退。CD4T细胞是否伴随着抗原递呈的逆行信号 随之而来的重新编程和未来的LEC功能未知。此外，表观遗传学的存在 LEC免疫记忆对后续LEC功能的转录切割程度和后果 被调查过了。因此，拟议的研究将确定参与免疫突触重塑LEC 肺炎期间的功能(K99)，并将测试CD4T细胞是否在LECs分解后产生训练有素的免疫 肺炎(R00)。拟议的目标将涉及使用单细胞测序技术，这是一种新颖的基因 设计的小鼠模型和创新的谱系追踪策略，以测试CD4T细胞是否重新编程 LEC抢占先机，抗击肺炎，并从中恢复。这些发现将统一粘膜免疫领域，LEC 生物学和肺再生，并有可能确定LECs作为免疫调节靶点，可以 受过抗击感染和癌症的训练，迅速修复肺部，并维持肺内平衡。