Defining the DNA damage pathway in faithful mitotic progression

项目总结/摘要 基因组不稳定性是癌症的标志，与患者总体预后不良相关。特定 基因组不稳定性的一种形式是染色体不稳定性（CIN），它发生在细胞连续错误分离时 它们的染色体导致核型的改变。CIN是癌症的常见特征-大约 90%的实体瘤和50%的造血系统癌症表现为CIN。CIN也与增加的 肿瘤进展和患者预后差。然而，CIN水平必须维持在最佳水平。 水平，因为太高水平的错误分离事件对细胞是有害的。这创造了一种治疗方法， 这是一个窗口，化疗可以利用CIN来创造有效的治疗癌细胞。商ATR DNA损伤修复途径的主要调节因子，通过促进DNA损伤修复确保基因组稳定性 及时复制。我最近发现ATR还通过促进忠实的 有丝分裂中染色体分离和预防CIN。在本申请中，我建议调查 ATR在有丝分裂中被激活的机制（Aim 1），识别其底物网络（Aim 2）并使用ATR 特异性靶向CIN癌细胞的抑制（Aim 3）。我提出的研究可能会揭示更多新的功能 ATR在有丝分裂中的作用，使我们能够更好地了解有丝分裂过程是如何被ATR和其他 DDR蛋白，以确保正确的染色体分离。这反过来又会让我们更好地了解 有丝分裂和DDR蛋白的重叠，以确保基因组的稳定性。最后，我希望制定一项战略， 特异性杀死CIN癌细胞将是靶向癌症治疗的突破。 我的职业目标是在一家领先的机构获得一个研究人员的职位，在那里我将剖析 ATR和其他DDR蛋白调节染色体分离的机制。我的成功转型 将通过增强我在细胞生物学，质谱和小鼠癌症模型方面的专业知识来支持。 我将使用这些获得的技能来研究ATR抑制剂是否可以用于特异性靶向CIN癌症 细胞重要的是，这个奖项为我提供的受保护的时间将允许我通过以下方式阐明机制： ATR被激活，并确定ATR抑制剂是否可用于利用癌细胞中的CIN。此外，委员会认为， 这个项目的成功将大大加强了我将建议我的优秀合作者 K22时期。这个奖项的接收将允许我扩大我的研究计划，并建立自己 作为癌症生物学领域的主要研究者。

PROJECT SUMMARY/ABSTRACT Genomic instability is a hallmark of cancer and correlated with overall poor patient prognosis. A specific form of genomic instability is chromosomal instability (CIN), which occurs when a cell continuously missegregate their chromosomes leading to changes in karyotype. CIN is a common feature of cancer – with approximately 90% of solid tumors and 50% of hematopoietic cancers exhibiting CIN. CIN is also correlated with increased tumor progression and poor patient prognosis. However, the levels of CIN must be maintained at an optimal level, because too high levels of missegregation events are deleterious to cells. This creates a therapeutic window by which chemotherapies can exploit CIN to create effective treatments against cancer cells. ATR, a master regulator of DNA damage repair pathways, ensures genomic stability by promoting DNA damage repair and timely replication. I recently showed that ATR also promotes genomic stability by promoting faithful chromosome segregation in mitosis and preventing CIN. In this application, I propose to investigate the mechanism by which ATR is activated in mitosis (Aim 1), identify its substrate network (Aim 2) and use ATR inhibition to target CIN cancer cells specifically (Aim 3). My proposed studies may reveal more novel functions of ATR in mitosis and allow us to better understand of how mitotic processes are regulated by ATR and other DDR proteins to ensure proper chromosome segregation. This in turn, will give us a better understanding of the overlap of mitotic and DDR proteins in ensuring genomic stability. Lastly, I hope that developing a strategy to specifically kill CIN cancer cells will be a breakthrough in targeted cancer therapies. My career goal is to obtain a research faculty position at a leading institution where I will dissect the mechanisms by which ATR and other DDR proteins regulate chromosome segregation. My successful transition would be bolstered by augmenting my expertise in cell biology, mass spectrometry and mouse cancer models. I will use these acquired skills to investigate whether ATR inhibitors can be used to specifically target CIN cancer cells. Importantly, the protected time that this award provides me will allow me to elucidate the mechanism by which ATR is activated and determine if ATR inhibitors can be used to exploit CIN in cancer cells. Furthermore, the success of this project will be greatly enhanced by the outstanding collaborators that I will have advise me through the K22 period. The receipt of this award will allow me to expand my research plan and establish myself as a primary investigator in the field of cancer biology.