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

基本信息

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
项目类别：
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

项目摘要

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具有自我更新的进化配置的机制，细胞群体的分化和多样化。但是，如果人类T细胞使用它，这是未知的诱导不同子细胞命运的机制。拟议的研究将检验以下假设不对称细胞分裂是人类T细胞的必不可少的机制，可以产生功能上不同的子细胞。实验将使用一种新型的免疫学诱导标记方法突触，多色流式细胞术，单细胞RNA测序和代谢组学分析，以识别和最终调节了支持本地和短暂进步的蜂窝程序基因设计的人T细胞。更好地了解细胞分裂模式将扩大我们的关于人T细胞分化的知识，发现促进小众特异性T细胞持久性的因素，以及建立生物学驱动的原理和方法来优化T细胞免疫疗法。候选人：Ellebrecht博士从德国卢贝克大学获得了医学博士学位，并将完成 2021年，宾夕法尼亚大学的皮肤病学居住培训。 Aimee Payne博士和Carl June博士在Penn的实验室培训。 5年的职业生涯开发计划包括结构化课程和单细胞转录分析中的培训，经验丰富的导师和合作者的生物信息学和人类T细胞的代谢分析，通过职业职业发展活动，目的是建立独立的NIH资助研究实验室研究皮肤和工程T细胞的命运诱导和寿命。环境：导师Aimee Payne博士和Carl June博士是NIH资助的宾夕法尼亚州调查员，谁在T细胞生物学，免疫疗法，代谢组学和单细胞中提供无与伦比的专业知识人类T细胞与包括先验K08和 K23获奖者。 Ellebrecht博士对皮肤居民不对称细胞分裂的关注T细胞提供了清晰的路径为了使他与Payne博士和June博士的关注转化免疫疗法区分开来。 Ellebrecht博士的研究和培训将得到宾夕法尼亚州皮肤科部门的支持细胞免疫疗法和CHOP代谢组学核心，为流动提供最新的核心设施细胞仪，细胞分选，单细胞测序，代谢组学，人体皮肤饰面和生物信息学。拍摄他的导师，合作者以及对这些一流技术的访问将共同创造理想 Ellebrecht博士在成为独立物理科学家的道路上蓬勃发展的环境领导和调节负责慢性炎症皮肤的T细胞群体的努力疾病。