Nrf2-mediated impaired hematopoietic stem cell fitness following irradiation

 描述（由申请人提供）：电离辐射（IR）暴露与癌症发病率增加的相关性已被认识超过100年，尽管其机制仍然知之甚少。IR诱导的癌症通常归因于由IR介导的DNA损伤导致的致癌突变的直接产生。我们的实验室已经开发了一种基于进化的致癌模型，它强调了细胞适应性作为肿瘤抑制的主要力量的作用。基本上，我们认为健康组织中的健康细胞非常善于维持现状，因为这些高度适应的细胞有效地与突变细胞竞争，使大多数潜在的致癌突变在克隆选择方面处于不利地位。从进化的角度来看，这种替代的自适应肿瘤发生模型预测，对组织适应性维持的投资应该是一种主要的肿瘤抑制策略，可以确保年轻人的罕见癌症发病率，从而增加生物种群的成功。我们提出，除了直接产生DNA损伤，IR暴露或其他损伤，通过降低细胞适应性，创造“改善的空间”，从而促进具有致癌突变的细胞的扩增，这些细胞在这种改变的背景下变得适应。使用小鼠模型，我们将测试IR暴露导致造血干细胞（HSC）中持续的Nrf2激活的假设，并且虽然Nrf2通过激活抗氧化剂参与者保护细胞免受过度损伤，但它也激活促分化参与者，从而导致干细胞丧失。我们还将探索在先前照射的HSC中持续Nrf2激活的机制，以及Notch等途径的激活如何逆转Nrf2激活并恢复自我更新。我们建议，这种Nrf2介导的“程序性免疫”，至少在更自然的情况下，偶尔的细胞损伤，促进从干细胞库中消除受损的细胞。维持干细胞库适应性应该是通过限制适应性致癌突变的选择来抑制肿瘤的。另一方面，在全身或整个组织辐射暴露的更现代背景下，几乎所有存活的干细胞都可能经历了遗传毒性应激，因此Nrf2依赖性“程序性遗传”将降低整个干细胞库的适应性（将缺乏更多的适应性竞争），这可以促进适应性致癌突变的选择。

 DESCRIPTION (provided by applicant): The association of ionizing radiation (IR) exposure with increased cancer incidence has been recognized for over 100 years, although the mechanism remains poorly understood. IR-induced cancers are conventionally attributed to the direct generation of cancer-causing mutations resulting from IR-mediated DNA damage. Our lab has developed an evolutionary based model for carcinogenesis, which instead highlights a role for cellular fitness as a major force in tumor suppression. Basically, we propose that healthy cells in a healthy tissue are very good at maintaining the status quo, as these highly fit cells effectively compete against mutant cells, rendering most potentially oncogenic mutations disadvantageous in terms of clonal selection. From an evolutionary standpoint, this alternative Adaptive Oncogenesis model predicts that investment in tissue fitness maintenance should be a major tumor suppressive strategy that ensures rare cancer incidence in the young, thus increasing organismal population success. We propose that besides direct generation of DNA damage, IR exposure or other insults, by decreasing cell fitness, create "room for improvement", and thus promote the expansion of cells with oncogenic mutations that become adaptive in this altered context. Using mouse models, we will test the hypothesis that IR exposure leads to sustained Nrf2 activation in hematopoietic stem cells (HSC), and that while Nrf2 protects cells from excessive damage by activating anti-oxidant players, it also activates pro-differentiation players, thus leading to loss of stemness. We will also explore the mechanism underlying sustained Nrf2 activation in previously irradiated HSC, as well as how the activation of pathways such as Notch can reverse Nrf2 activation and restore self-renewal. We propose that this Nrf2-mediated "programmed mediocrity", at least in the more natural context of damage to the occasional cell, facilitates the elimination of the damaged cell from the stem cell pool. Maintaining stem cell pool fitness should be tumor suppressive by limiting selection for adaptive oncogenic mutations. On the other hand, under the more modern context of total body or whole tissue radiation exposure, virtually all surviving stem cells may have experienced genotoxic stress, and thus the Nrf2-dependent "programmed mediocrity" will reduce the fitness of the entire stem cell pool (more fit competition will be lacking), which can promote selection for adaptive oncogenic mutations.