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：
10660920
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/10660920
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 Dedications 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 Infiltration 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 Predisposition 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 Tumor Promotion Virus Diseases Work age effect age related aged anticancer research 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

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。癌症发病率随着年龄的增长而急剧增加。虽然平均预期寿命继续上升，其后果之一是癌症病例预计在 2010 年至 2030 年间将增加 45%，这凸显迫切需要研究衰老生理学与肿瘤发生之间的交叉点。然而，大多数癌症研究是使用年轻成年小鼠作为临床前癌症模型进行的，其中无法测量影响肿瘤发生关键特征的环境风险因素，例如衰老。免疫随着年龄的增长，系统特别容易出现功能衰退。许多不同种类的免疫细胞可以发现浸润性肿瘤，其中 CD8+ T 细胞尤其可以通过以下方式识别并选择性杀死癌细胞：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 CD8+ T 细胞增殖和效应反应，衰老对抗衰老的作用肿瘤免疫仍然是一个主要的黑匣子。根据我们对年轻和老年小鼠肿瘤的初步数据，我们假设 CD8+ T 细胞的抗肿瘤免疫受损导致衰老过程中肿瘤的发生。到为了检验这一假设，Aim 1将首先开发小鼠模型来研究衰老、癌症和抗肿瘤免疫，以及然后使用流式细胞术和单细胞确定改变肿瘤微环境中免疫细胞功能的机制 RNA测序。在目标 2 中，我们将定义衰老肿瘤微环境中的代谢变化，然后进行测试这些是否是 CD8+ T 细胞功能障碍的原因。最后，目标 3 将确定是否增强新陈代谢通过转录组学和代谢组学分析鉴定的免疫细胞通路可以改善肿瘤控制老化期间。通过揭示肿瘤微环境如何随年龄变化及其对抗肿瘤的影响免疫，这些研究将确定驱动肿瘤中 T 细胞功能障碍的机制，这些机制可能针对改善癌症的预防和治疗。候选人。 Alison Ringel 博士是这项研究计划的 PI。她曾担任博士后研究员在过去的五年里，她在哈佛医学院学习，试图了解分子生物学响应肥胖等环境癌症危险因素而驱动肿瘤发生的机制。她是在面试终身教授职位的过程中，并制定了详细的专业发展计划将使她能够过渡到独立研究职业，在那里她将发展自己衰老和肿瘤发生的研究计划。她的目标是通过应用成为癌症免疫学领域的领导者一种创新的系统生物学方法来剖析肿瘤生态位，这将使她的独立工作与众不同来自她的博士后导师。她的长期目标是领导一个独立的癌症研究项目致力于发现肿瘤内调节局部免疫反应的分子机制肿瘤进展。