Asymmetric cell division for fate commitment of human T cells

人类 T 细胞命运决定的不对称细胞分裂

• 批准号: 10349746
• 负责人: Christoph Thomas Ellebrecht
• 金额: $ 17.33万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10349746
• 关键词: Affect; Bioinformatics; Biology; Blood; Cell Separation; Cell division; Cells; Cellular biology; Cellular immunotherapy; Clinical; Core Facility; Data; Daughter; Dermatology; Development; Development Plans; Distal; Effector Cell; Engineering; Environment; FOXO1A gene; Flow Cytometry; Functional disorder; Funding; Gene Expression Profile; Gene Expression Profiling; Genetic Engineering; Genetic Transcription; Germany; Goals; Human; Human Engineering; Immunotherapy; In Situ; In Vitro; Infection; Inflammatory; Knowledge; Label; Laboratories; Laboratory Research; Longevity; Memory; Mentors; Metabolic; Metabolic Pathway; Metabolism; Methods; Mitochondria; Mitosis; Molecular; Mus; Outcome; Pathway interactions; Pattern; Pennsylvania; Pharmacology; Phenotype; Physicians; Population; Research; Research Personnel; Research Training; Residencies; Scientist; Signal Pathway; Signal Transduction; Skin; Structure; T cell differentiation; T memory cell; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; TCR Activation; Technology; Testing; Therapeutic; Tissues; Training; United States National Institutes of Health; Universities; Xenograft Model; base; career development; chimeric antigen receptor; chimeric antigen receptor T cells; chronic inflammatory skin; daughter cell; design; effector T cell; engineered T cells; exhaustion; experience; experimental study; fatty acid oxidation; genetic manipulation; human disease; immunological synapse; improved; in vivo; innovation; lymphoid organ; metabolomics; mouse model; notch protein; novel; pathogen; post-doctoral training; pre-clinical; programs; public health relevance; self-renewal; single cell sequencing; single-cell RNA sequencing; skin disorder; skin xenograft

Project Abstract Research: Asymmetric cell division is an evolutionarily conserved mechanism that affords self-renewal, differentiation and diversification of cell populations. It is unknown, however, if human T cells use this mechanism to induce distinct daughter cell fates. The proposed research will test the hypothesis that asymmetric cell division is an indispensable mechanism of human T cells to generate functionally distinct daughter cells. The experiments will use a novel method of target-induced labeling of the immunological synapse, multicolor flow cytometry, single cell RNA sequencing and metabolomic profiling to identify and ultimately modulate cellular programs that support long- and short-lived progeny induction in both native and genetically-engineered human T cells. A better understanding of cell division patterns will expand our knowledge on human T cell differentiation, uncover factors promoting niche-specific T cell persistence, and establish biology-driven principles and methods for optimization of T cell immunotherapy. Candidate: Dr. Ellebrecht earned his MD from the University of Lubeck, Germany and will complete Dermatology residency training at the University of Pennsylvania in 2021. Dr. Ellebrecht is pursuing postdoctoral training in Dr. Aimee Payne’s and Dr. Carl June’s laboratories at Penn. The 5-year career development plan includes structured coursework and training in single cell transcriptional profiling, bioinformatics, and metabolic profiling of human T cells from experienced mentors and collaborators, along with professional career development activities, with the goal of establishing an independent, NIH-funded research laboratory investigating fate induction and longevity of skin-resident and engineered T cells. Environment: The mentors, Dr. Aimee Payne and Dr. Carl June, are renowned NIH-funded Penn investigators, who provide unparalleled expertise in T cell biology, immunotherapy, metabolomics and single cell characterization of human T cells in combination with an exceptional mentoring record including prior K08 and K23 awardees. Dr. Ellebrecht’s focus on asymmetric cell division in skin resident T cells provides a clear path to independence that sets him apart from Dr. Payne’s and Dr. June’s focus on translational immunotherapy. Dr. Ellebrecht’s research and training will be supported by the Penn Dermatology Department, Center for Cellular Immunotherapy and CHOP metabolomics core, providing state-of the-art core facilities for flow cytometry, cell sorting, single cell sequencing, metabolomics, human skin xenografts and bioinformatics. Taken together, his mentors, collaborators and access to these top-notch technologies will create an ideal environment for Dr. Ellebrecht to thrive on his path towards becoming an independent physician scientist leading efforts to characterize and modulate T cell populations responsible for chronic inflammatory skin diseases.

项目摘要 研究：不对称细胞分裂是一种进化上保守的机制，提供自我更新， 细胞群体的分化和多样化。然而，目前尚不清楚人类T细胞是否使用这种方法 诱导不同子代细胞命运的机制。这项拟议的研究将检验这一假设 细胞不对称分裂是人类T细胞产生不同功能的不可或缺的机制 子代细胞。这些实验将使用一种新的靶向诱导免疫标记方法。 突触、多色流式细胞术、单细胞RNA测序和代谢组谱分析 最终调节支持长寿和短命后代诱导的细胞程序 经过基因工程的人类T细胞。对细胞分裂模式的更好理解将扩大我们的 了解人类T细胞分化，发现促进利基特异性T细胞持续存在的因素，以及 建立生物驱动的优化T细胞免疫治疗的原则和方法。 候选人：Ellebrecht博士在德国吕贝克大学获得医学博士学位，将完成 2021年在宾夕法尼亚大学进行皮肤科住院医师培训。埃勒布雷希特博士正在追查 在艾米·佩恩博士和卡尔·琼博士在宾夕法尼亚大学的实验室进行博士后培训。五年职业生涯 发展计划包括有组织的课程作业和单细胞转录图谱培训， 来自有经验的导师和合作者的人类T细胞的生物信息学和代谢概况，以及 与专业的职业发展活动，目标是建立一个独立的，由NIH资助的 研究皮肤常驻T细胞和工程T细胞的命运诱导和寿命的研究实验室。 环境：导师艾米·佩恩博士和卡尔·琼博士是美国国立卫生研究院资助的宾夕法尼亚大学著名的调查人员， 他们在T细胞生物学、免疫治疗、代谢组学和单细胞方面提供了无与伦比的专业知识 人类T细胞的特征结合特殊的指导记录，包括先前的K08和 K23获奖者。Ellebrecht博士对皮肤常驻T细胞的不对称细胞分裂的关注提供了一条清晰的途径 独立，这让他有别于佩恩博士和琼博士对转化性免疫疗法的关注。 Ellebrecht博士的研究和培训将得到宾夕法尼亚大学皮肤科中心的支持 细胞免疫治疗和CHOP代谢组学核心，为FLOW提供最先进的核心设施 细胞学、细胞分选、单细胞测序、代谢组学、人体皮肤移植和生物信息学。已被占用 他的导师、合作者和对这些顶尖技术的接触将共同创造一个理想 埃勒布雷希特博士在成为独立内科科学家的道路上茁壮成长的环境 领导鉴定和调节导致慢性炎症性皮肤的T细胞群的努力 疾病。