Amy Briggs Diversity Supplement R01AG067584

艾米·布里格斯多样性补充 R01AG067584

• 批准号: 10273522
• 负责人: James V Degregori
• 金额: $ 3.06万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10273522
• 关键词: Acute Myelocytic Leukemia; Age; Aging; B-Lymphocytes; Bone Marrow; Cell Compartmentation; Cells; Development; Elderly; Event; Evolution; Funding; Hematopoiesis; Hematopoietic; Hematopoietic Neoplasms; Impairment; Inflammation; Inflammatory; Intervention; Life; Link; Malignant Neoplasms; Mutation; Oncogenic; Phenotype; Population; Prevention; Risk; Role; Testing; Tissues; aged; environmental change; fitness; human old age (65+); leukemia; leukemogenesis; mouse model; senescence; stem; stem cells; tumorigenesis

The risk of most cancers, including leukemias, increases exponentially as we age, with over 90% of cancers occurring after the age of 50. This association has been primarily ascribed to the gradual accumulation of mutations throughout life. We contend that the contribution of mutations (while necessary) is not sufficient to explain the role of aging in the development of leukemias and other cancers. Just as species evolution has been driven by environmental changes that select for adaptive phenotypes in populations, we propose that the changes in our tissues known to occur in old age are substantial contributors to oncogenesis. Inflammation and senescent cells increase in the bone marrow of the elderly, which along with other changes contribute to impaired hematopoiesis. In the current funding period, we have used mouse models to show that the aged and inflammatory bone marrow microenvironment reduces the fitness of B- cell progenitors, promoting selection for particular adaptive oncogenic events, leading to increased leukemogenesis in these contexts. Here, we will explore how changes in hematopoietic stem and early progenitor cell (HSPC) pools driven by microenvironmental alterations in old age influence selection on oncogenic events known to initiate acute myeloid leukemias. We will also develop interventions to reduce microenvironmental perturbations and associated oncogenesis in old age. Our central hypothesis is that aging-dependent increases in inflammation and senescent cells are critical for enhancing selection for oncogenic mutations that occur throughout life, and that dampening inflammation and/or removing senescent cells can reduce the risk of the associated leukemias. To test our hypothesis, we will pursue two aims: 1) Determine how aging, inflammation and senescence influence oncogenic adaptation in the HSPC compartment and 2) Identify the mechanisms underlying increased oncogenesis in aged HSPC pools. By determining whether and how microenvironmental changes impact HSPC fitness and thus oncogenic adaptation in old age, these results could provide a new explanation for links between aging and leukemia risk. In all, proposed studies could provide answers for fundamental questions: Why do we get more leukemias as we age? Why are particular oncogenic mutations selected for in the bone marrow of the elderly? Can we alter aging-associated positive selection for oncogenic events and thus reduce leukemia risk? These studies could suggest interventions that can reduce the risk of hematopoietic malignancies of old age by manipulating specific factors in the bone marrow microenvironment.

随着年龄的增长，包括白血病在内的大多数癌症的风险呈指数级增加， 超过90%的癌症发生在50岁以后。这种联系主要归因于 到生命中突变的逐渐积累。我们认为， 突变（虽然必要）不足以解释衰老在发展中的作用。 白血病和其他癌症。正如物种进化是由环境驱动的 在种群中选择适应性表型的变化，我们建议，我们的变化， 已知在老年出现的组织是肿瘤发生的重要贡献者。炎症和 老年人骨髓中衰老细胞增多，这沿着着其他变化 导致造血功能受损在当前的资助期内，我们使用了小鼠模型， 表明老化和炎症的骨髓微环境降低了B- 细胞祖细胞，促进特定适应性致癌事件的选择，导致 在这些情况下增加白血病的发生。在这里，我们将探讨造血系统的变化 干细胞和早期祖细胞（HSPC）池由老年微环境改变驱动 影响对已知引发急性髓性白血病致癌事件的选择。我们还将 制定干预措施，以减少微环境扰动和相关的肿瘤发生 在老年。我们的中心假设是，炎症和炎症反应的年龄依赖性增加， 衰老细胞对于增强对致癌突变的选择至关重要， 并且抑制炎症和/或去除衰老细胞可以降低衰老的风险。 相关的白血病为了验证我们的假设，我们将追求两个目标：1）确定如何老化， 炎症和衰老影响HSPC隔室中的致癌适应，以及2） 确定老年HSPC合并物中肿瘤发生增加的潜在机制。 通过确定微环境变化是否以及如何影响HSPC适应性， 因此，这些结果可以为老年人的致癌适应提供新的解释， 衰老和白血病风险之间的联系总而言之，拟议的研究可以为基本问题提供答案。 问题：为什么随着年龄的增长，我们会患上更多的白血病？为什么特定的致癌突变 选择在老年人的骨髓中？我们能改变衰老相关的正选择吗 从而降低白血病的风险这些研究可以建议干预措施 可以通过操纵特定因素来降低老年人患造血系统恶性肿瘤的风险 在骨髓微环境中。