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: 10747632
• 负责人: Anukul T Shenoy
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10747632
• 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 Reprogramming; Cell Separation; Cell physiology; Cells; Cellular biology; Clinical; Committee Members; Communication; Communities; Computational Biology; Data; Data Set; Disease; Ensure; Epigenetic Process; Epithelial Cell Proliferation; Epithelial Cells; Etiology; Faculty; Future; 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; Modeling; Mucosal Immunity; Mucous Membrane; Mus; Myeloid Cells; Neutrophil Infiltration; PD-1/PD-L1; Patients; Phenocopy; Pneumococcal Pneumonia; Pneumonia; Postdoctoral Fellow; Recombinants; Recurrence; Reporting; Research; Resolution; Role; Scientist; Signal Transduction; Sorting; Streptococcus pneumoniae; T-Lymphocyte; Technology; Testing; Tissues; Training; Universities; Work; antigen test; antimicrobial; career; career development; cell regeneration; cytokine; empowerment; epigenome; 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; programs; 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.

项目概要 候选人信息：我是波士顿大学肺科医学院 Joseph Mizgerd 博士实验室的博士后研究员 自 2018 年 1 月起在该中心工作，我的工作重点是阐明肺上皮细胞 (LEC) 和 CD4 T 细胞如何 肺炎球菌期间相互沟通以优化细菌清除和组织弹性 我的职业目标是成为顶级学术机构的终身教职人员， 培训学术阶梯各阶层的科学家（包括本科生、研究生和博士后） 研究不同细胞相互作用对肺免疫和修复的影响的机制和后果 应对各种感染、过敏、癌症和衰老。 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- 以及长期的研究和培训目标，我组建了一个由博士组成的指导团队。 Joseph Mizgerd（导师）和 Darrell Kotton 博士（联合导师）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并取得进步 熟练掌握肺上皮细胞和干细胞生物学、单细胞测序和计算生物学， 和肺部免疫学，以及对癌症生物学和 T 细胞生物学的更多了解。 委员会成员将定期与我进行一对一讨论和大型委员会会议，以确保 我严格的研究和职业发展培训将帮助我以独特的方式过渡到独立。 这套技能使我能够成为健康和疾病期间 LEC-CD4 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驻留记忆 CD4 T (TRM) 细胞在再感染期间通过重塑 LEC 反应来赋予抗微生物免疫力。 初步数据表明，LEC 和干细胞能够在细胞增殖过程中将抗原呈递给 CD4 T 细胞。 肺炎，然后对过去与 CD4 T 细胞接触的自主免疫记忆 肺炎的缓解是否伴随抗原呈递至 CD4 T 细胞的逆行信号传导。 此外，LEC 的伴随功能和未来功能是否存在、表观遗传和功能尚不清楚。 LEC 免疫记忆对后续 LEC 功能的转录组范围和影响从未 因此，拟议的研究将确定免疫突触的参与是否会重塑 LEC。 在肺炎期间发挥功能 (K99)，并将测试 CD4 T 细胞在消退后是否在 LEC 中产生免疫力 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测序技术。 工程小鼠模型和创新的谱系追踪策略来测试 CD4 T 细胞是否重新编程 LEC 预防肺炎、对抗肺炎并从中恢复的研究结果将统一粘膜免疫、LEC 领域。 生物学和肺再生，并有可能将 LEC 确定为免疫调节靶点 接受培训以对抗感染和癌症，及时修复肺部并维持肺稳态。