Cellular and microenvironmental mechanisms linking aging to tumor control

将衰老与肿瘤控制联系起来的细胞和微环境机制

基本信息

批准号：
10348456
负责人：
Alison Epstein Ringel
金额：
$ 16.2万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
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：
2022-07-11 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10348456
关键词：
Affect Age Aging Applications Grants Atlases Bacterial Infections Beds Bioenergetics Biological Models CD8-Positive T-Lymphocytes Cancer Model Cancer Research Project Cell Culture Techniques Cell physiology Cells Data Development Plans Doctor of Philosophy Elderly Environmental Impact Environmental Risk Factor Enzymes Faculty Fatty acid glycerol esters Flow Cytometry Functional disorder Future Genes Genetic Transcription Goals Growth Heterogeneity Immune Immune response Immune system Impairment In Vitro Incidence Interview Laboratories Lead Life Expectancy Link Lipids Malignant Neoplasms Manuscripts Maps Measures Mediating Mentors Metabolic Metabolic Pathway Modeling Molecular Mus Mutation Newly Diagnosed Normal tissue morphology Obese Mice Obesity Pathway interactions Patients Physiology Population Positioning Attribute Postdoctoral Fellow Prevention therapy Process Publishing Research Research Proposals Risk Factors Role Stress Stromal Cells Systems Biology T-Cell Activation T-Cell Proliferation T-Lymphocyte Testing Therapeutic Time Tumor Immunity Virus Diseases Work age effect age related aged anticancer research base cancer cell cancer diagnosis cancer prevention cancer risk cancer therapy career cell age cell killing cell type comparative diet-induced obesity environment related cancer functional decline healthy aging human old age (65+)immune function improved in vivo innovation insight lipid biosynthesis lipid mediator lipidomics medical schools metabolomics mouse model neoplastic cell overexpression patient population pre-clinical programs response single-cell RNA sequencing tenure track transcriptomics tumor tumor growth tumor immunology tumor microenvironment tumor progression tumorigenesis young adult

Affect Age Aging Applications Grants Atlases Bacterial Infections Beds Bioenergetics Biological Models CD8-Positive T-Lymphocytes Cancer Model Cancer Research Project Cell Culture Techniques Cell physiology Cells Data Development Plans Doctor of Philosophy Elderly Environmental Impact Environmental Risk Factor Enzymes Faculty Fatty acid glycerol esters Flow Cytometry Functional disorder Future Genes Genetic Transcription Goals Growth Heterogeneity Immune Immune response Immune system Impairment In Vitro Incidence Interview Laboratories Lead Life Expectancy Link Lipids Malignant Neoplasms Manuscripts Maps Measures Mediating Mentors Metabolic Metabolic Pathway Modeling Molecular Mus Mutation Newly Diagnosed Normal tissue morphology Obese Mice Obesity Pathway interactions Patients Physiology Population Positioning Attribute Postdoctoral Fellow Prevention therapy Process Publishing Research Research Proposals Risk Factors Role Stress Stromal Cells Systems Biology T-Cell Activation T-Cell Proliferation T-Lymphocyte Testing Therapeutic Time Tumor Immunity Virus Diseases Work age effect age related aged anticancer research base cancer cell cancer diagnosis cancer prevention cancer risk cancer therapy career cell age cell killing cell type comparative diet-induced obesity environment related cancer functional decline healthy aging human old age (65+)immune function improved in vivo innovation insight lipid biosynthesis lipid mediator lipidomics medical schools metabolomics mouse model neoplastic cell overexpression patient population pre-clinical programs response single-cell RNA sequencing tenure track transcriptomics tumor tumor growth tumor immunology tumor microenvironment tumor progression tumorigenesis young adult

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项目摘要

Project Summary. Research. Cancer incidence increases dramatically with age. While the average life expectancy continues to rise, one consequence is that cancer cases are predicted to grow by 45% between 2010 and 2030, highlighting the critical need to study the intersection between aging physiology and tumorigenesis. However, the majority of cancer research is performed using young adult mice as pre-clinical cancer models, where impact of environmental risk factors, like aging, on key features of tumorigenesis cannot be measured. The immune system is especially vulnerable to functional decline with aging. Many different kinds of immune cells can be found infiltrating tumors, where CD8+ T cells in particular can identify and selectively kill cancer cells by recognizing tumor features that differ from normal tissue. Although studies have shown that aging diminishes CD8+ T cell proliferation and effector responses following bacterial and viral infections, the role of aging on anti- tumor immunity is still a major black box. Based on our preliminary data in tumors from young and aged mice, we hypothesize that impaired anti-tumor immunity by CD8+ T cells contributes to tumorigenesis during aging. To test this hypothesis, Aim 1 will first develop mouse models to study aging, cancer, and anti-tumor immunity, and then identify mechanisms that alter immune cell function in the tumor niche using flow cytometry and single cell RNA-sequencing. In Aim 2, we will define metabolic changes in the aged tumor microenvironment and then test whether these are causal for CD8+ T cell dysfunction. Finally, Aim 3 will determine whether enhancing metabolic pathways in immune cells identified by transcriptomic and metabolomic analysis can improve tumor control during aging. By revealing how the tumor microenvironment changes with age and the impact on anti-tumor immunity, these studies will identify mechanisms that drive T cell dysfunction in tumors that may be targeted to improve cancer prevention and therapy. Candidate. Dr. Alison Ringel, PhD, is the PI for this research proposal. She has worked as a postdoctoral fellow for the past five years at Harvard Medical School, where she has sought to understand the molecular mechanisms that drive tumorigenesis in response to environmental cancer risk factors such as obesity. She is in the process of interviewing for tenure-track faculty positions and has mapped out a detailed professional development plan that will enable her to transition to an independent research career where she will develop her research program on aging and tumorigenesis. She aims to become a leader in cancer immunology by applying an innovative systems biology approach to dissect the tumor niche, which will distinguish her independent work from that of her postdoctoral mentors. Her long-term goal is to lead an independent cancer research program dedicated to the discovery of molecular mechanisms within tumors that regulate local immune responses and tumor progression.

项目摘要。研究。癌症的发病率随着年龄的增长而大大增加。而平均预期寿命则继续上升，结果是，预计在2010年至2030年间，预计癌症病例将增长45％研究衰老生理学和肿瘤发生之间的交集的迫切需要。但是，大多数使用年轻小鼠作为临床前癌症模型进行癌症研究无法测量有关肿瘤发生的关键特征（例如衰老）的环境危险因素。免疫系统特别容易受到衰老的功能下降。许多不同种类的免疫细胞可以是发现浸润肿瘤，特别是CD8+ T细胞可以通过识别与正常组织不同的肿瘤特征。尽管研究表明衰老会减少细菌和病毒感染后的CD8+ T细胞增殖和效应子反应，衰老对抗 - 的作用肿瘤免疫仍然是一个主要的黑匣子。根据我们在年轻小鼠和老年小鼠的肿瘤中的初步数据，我们假设CD8+ T细胞受损的抗肿瘤免疫受损会导致衰老期间的肿瘤发生。到检验该假设，AIM 1将首先开发小鼠模型来研究衰老，癌症和抗肿瘤免疫力，并然后确定使用流式细胞术和单细胞的机制改变肿瘤生态位的免疫细胞功能 RNA测序。在AIM 2中，我们将定义老化肿瘤微环境的代谢变化，然后测试这些是否是CD8+ T细胞功能障碍的因果关系。最后，AIM 3将决定是否增强新陈代谢通过转录组和代谢组分析鉴定的免疫细胞中的途径可以改善肿瘤对照在衰老期间。通过揭示肿瘤微环境如何随着年龄的增长而变化以及对抗肿瘤的影响免疫力，这些研究将确定在肿瘤中驱动T细胞功能障碍的机制改善癌症预防和治疗。候选人。 Alison Ringel博士博士是该研究建议的PI。她曾担任博士后研究员在过去的五年中，哈佛医学院试图了解分子响应环境癌症危险因素（例如肥胖症）的机制。她是在采访任期教师职位的过程中，并绘制了一个详细的专业人士开发计划将使她能够过渡到独立的研究职业，在那里她将发展她衰老和肿瘤发生研究计划。她的目标是通过申请成为癌症免疫学的领导者一种创新的系统生物学方法来剖析肿瘤生态位，该方法将区分她的独立工作从她的博士后导师那里。她的长期目标是领导独立的癌症研究计划致力于发现调节局部免疫反应和肿瘤进展。