BubRI in Cancer and Aging

项目摘要/摘要 年龄是癌症和其他衰弱或危及生命的疾病的最重要的风险因素，但如何 生物过程在分子水平上随着年龄的变化而变化，以及这些变化如何影响细胞， 组织和器官功能障碍在很大程度上仍是未知的。填补我们知识中的这些空白对于 了解癌症和衰老。罕见的常染色体隐性儿童疾病，以癌症为特征 和早衰，如马赛克杂色非整倍体(MVA)综合征，越来越被认为是 强大的工具，促进关于癌症-衰老交界处的基本生物过程的知识。 大多数MVA病例与BUBR1的突变有关，BUBR1是正常染色体所需的有丝分裂检查点基因 种族隔离。我们的长期目标是发现BubR1的全部生物学功能，定义如何 BubR1的缺陷会导致癌症和其他与衰老相关的疾病的发展，并应用 由此获得的信息将用于开发创新的治疗策略，从而为许多人带来更好的健康。AS 在追求这一目标的下一步，我们的目标是机械地理解BubR1如何 缺乏诱导细胞衰老，并增强生长因子受体(GFR)信号，以推动年龄- 相关的癌变，并评估非整倍体和衰老是否由BubR1基因异常引起 启动免疫监视机制。根据我们的初步数据，我们假设BubR1 不足通过Wnt/β-连环蛋白信号的非计划激活来推动细胞衰老，促进 通过破坏GFR内吞作用促进肿瘤生长，并参与cGAS-Sting胞浆DNA传感通路 作为一种故障保护机制，通过免疫系统消除衰老和非整倍体细胞。我们建议 通过追求三个具体目标来检验这一假设。在第一个目标中，我们将确定BubR1不足是如何 使用抑制β的药理学和遗传学方法促进衰老介导的过早衰老- BubR1程序性小鼠的连接素活性。在第二个目标中，我们将确定BubR1是否以及如何 利用MVA患者细胞系和MVA研究肿瘤相关GFRs的内化 老鼠模型。在第三个目标中，我们将通过以下方式评估细胞质基因组dna传感的活体相关性 利用BubR1缺乏小鼠模型研究cGAS-Sting在衰老、异倍体、癌症和衰老中的作用 与Sting基因敲除小鼠相结合的染色体不稳定。这一创新技术的预期总体影响 它将垂直推进我们对一种显著的有丝分裂检查点蛋白如何 预防癌症和衰老这两个重大人类健康问题的保障措施，以及BubR1的缺陷 扰乱其在细胞内的多方面功能。重要的是，预计结果将产生积极影响 因为它们可能会为治疗或预防艾滋病的革命性临床干预铺平道路 广泛的人类癌症和限制健康寿命的与年龄相关的疾病的子集，此外 从概念上推进有丝分裂、信号、癌症和衰老等领域。

PROJECT SUMMARY/ABSTRACT Age is the most important risk factor for cancer and other debilitating or life-threatening conditions, but how biological processes change with aging at the molecular level and how these changes contribute to cellular, tissue, and organismal dysfunction remain largely unknown. Filling these gaps in our knowledge is critical for understanding both cancer and aging. Rare autosomal-recessive childhood disorders characterized by cancer and premature aging, such as Mosaic Variegated Aneuploidy (MVA) syndrome, are increasingly recognized as powerful tools for advancing knowledge about fundamental biological processes at the cancer-aging interface. Most MVA cases are linked to mutations in BUBR1, a mitotic checkpoint gene required for proper chromosome segregation. Our long-term goal is to uncover the full spectrum of BubR1 biological functions, define how deficiencies in BubR1 contribute to the development of cancer and other aging-related diseases, and apply the information thus gained to develop innovative therapeutic strategies that will lead to better health for many. As the next step in the pursuit of this goal, our objective here is to understand mechanistically how BubR1 insufficiencies induce cellular senescence and enhance growth factor receptor (GFR) signaling to drive age- related carcinogenesis, and to assess whether aneuploidy and senescence resulting from BubR1 aberrancies activate immune surveillance mechanisms. Based on our preliminary data, we hypothesize that BubR1 insufficiencies drive cellular senescence through unscheduled activation of Wnt/β-catenin signaling, promote neoplastic growth by disrupting GFR endocytosis, and engage the cGAS-Sting cytosolic DNA sensing pathway as a fail-safe mechanism to eliminate senescent and aneuploid cells via the immune system. We propose to test this hypothesis by pursuing three specific aims. In the first aim, we will determine how BubR1 insufficiency drives senescence-mediated premature aging using pharmacological and genetic approaches to inhibit β- catenin activity in BubR1 progeroid mice. In the second aim, we will establish whether and how BubR1 insufficiencies impair internalization of cancer-associated GFRs by using MVA patient cell lines and MVA mouse models. In the third aim, we will assess the in vivo relevance of cytoplasmic genomic DNA sensing by cGas-Sting in senescence, aneuploidization, cancer and aging using mouse models for BubR1 insufficiency and chromosomal instability combined with Sting knockout mice. The expected overall impact of this innovative proposal is that it will vertically advance our understanding of how a prominent mitotic checkpoint protein safeguards against two significant human health problems, cancer and aging, and how deficiencies of BubR1 disrupt its multifaceted functions in the cell. Importantly, the results are expected to have a positive impact because they will likely pave the way towards transformative clinical interventions for treating or preventing a broad spectrum of human cancers and a subset of age-related diseases that limit healthy lifespan, in addition to conceptually advancing the fields of mitosis, signaling, cancer, and aging.