权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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进化上保守的机制，可提供自我更新、细胞群的分化和多样化。然而，尚不清楚人类 T 细胞是否使用这种方法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细胞产生功能独特的不可缺少的机制子细胞。该实验将使用一种新的免疫学靶标诱导标记方法突触、多色流式细胞术、单细胞 RNA 测序和代谢组学分析来识别和最终调节细胞程序，支持本地和短期后代诱导的长寿命和短寿命基因工程人类T细胞。更好地了解细胞分裂模式将扩大我们的研究范围关于人类 T 细胞分化的知识，揭示促进利基特异性 T 细胞持久性的因素，以及建立优化 T 细胞免疫治疗的生物学驱动原则和方法。候选人：Ellebrecht 博士在德国吕贝克大学获得医学博士学位，并将完成 2021 年在宾夕法尼亚大学接受皮肤科住院医师培训。Ellebrecht 博士正在追求在宾夕法尼亚大学 Aimee Payne 博士和 Carl June 博士的实验室进行博士后培训。 5年职业生涯发展计划包括单细胞转录分析的结构化课程和培训，来自经验丰富的导师和合作者的人类 T 细胞的生物信息学和代谢分析，以及开展专业职业发展活动，目标是建立一个由 NIH 资助的独立机构研究实验室研究皮肤驻留和工程 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 资助的宾夕法尼亚大学著名研究人员，他们在 T 细胞生物学、免疫治疗、代谢组学和单细胞领域提供无与伦比的专业知识人类 T 细胞的表征与卓越的指导记录相结合，包括之前的 K08 和 K23 获奖者。 Ellebrecht 博士对皮肤驻留 T 细胞的不对称细胞分裂的关注提供了一条清晰的道路独立性使他与佩恩博士和琼博士专注于转化免疫疗法不同。 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，为流程提供最先进的核心设施细胞计数、细胞分选、单细胞测序、代谢组学、人类皮肤异种移植和生物信息学。采取他的导师、合作者和这些顶尖技术的共同努力将创造一个理想的为 Ellebrecht 博士在成为一名独立医师科学家的道路上茁壮成长提供了良好的环境领导研究和调节导致慢性炎症性皮肤的 T 细胞群的工作疾病。