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

• 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
• 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

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保持在 上升，一个后果是癌症病例预计将在2010至2030年间增长45%，突显出 迫切需要研究衰老生理学和肿瘤发生之间的交集。然而，大多数人 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 环境风险因素，如衰老，对肿瘤发生的关键特征无法测量。免疫者 随着年龄的增长，系统特别容易受到功能衰退的影响。许多不同种类的免疫细胞可以 发现浸润性肿瘤，其中CD8+T细胞可以识别并选择性地通过 识别不同于正常组织的肿瘤特征。尽管研究表明，衰老会减少 细菌和病毒感染后CD8+T细胞的增殖和效应反应，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细胞的抗肿瘤免疫功能受损在衰老过程中参与了肿瘤的发生。至 验证这一假设，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 然后使用流式细胞仪和单细胞分析来确定改变肿瘤巢内免疫细胞功能的机制 RNA测序。在目标2中，我们将定义老年肿瘤微环境中的代谢变化，然后测试 这些是否是CD8+T细胞功能障碍的原因。最后，目标3将决定是否增强新陈代谢 通过转录和代谢分析确定免疫细胞中的途径可以改善肿瘤控制 在衰老过程中。通过揭示肿瘤微环境如何随年龄变化以及对抗肿瘤的影响 免疫，这些研究将确定驱动肿瘤中T细胞功能障碍的机制，这些机制可能是 提高癌症防治水平。 候选人。艾莉森·林格尔博士是这项研究提案的PI。她一直担任博士后研究员。 在过去的五年里，她一直在哈佛医学院寻求了解分子 促进肿瘤发生的机制是对环境癌症风险因素的反应，如肥胖。她是 在面试终身教职的过程中，并制定了详细的专业 发展计划，使她能够过渡到独立的研究生涯，在那里她将发展她的 衰老和肿瘤发生的研究计划。她的目标是成为癌症免疫学的领导者，通过应用 一种创新的系统生物学方法来解剖肿瘤利基，这将使她的独立工作与众不同 与她的博士后导师们的观点不同。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和 肿瘤进展。