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Defining the DNA damage pathway in faithful mitotic progression

定义忠实有丝分裂进展中的 DNA 损伤途径

基本信息

批准号：
10177975
负责人：
Lilian Carolina Kabeche
金额：
$ 18.62万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-02 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10177975
关键词：
ATR gene Affect Aneuploidy Award Binding Breast cancer metastasis Cancer Biology Cancer Model Cancer cell line Cell Cycle Arrest Cell Line Cells Cellular biology Centromere Cessation of life Chromosomal Instability Chromosome Segregation Chromosomes Congenital Abnormality DNA Damage DNA Repair DNA biosynthesis Defect Diploidy Drug resistance Ensure Event Exhibits Genetic Materials Genetic Variation Genome Stability Genomic Instability Goals Hematologic Neoplasms Immune Immune Evasion Institution Interphase Karyotype Lead Link Malignant Neoplasms Malignant neoplasm of ovary Mass Spectrum Analysis Mediator of activation protein Mitosis Mitotic Mus Neoplasm Metastasis Organism Pathway interactions Patients Phenotype Phosphotransferases Population Positioning Attribute Process Prognosis Proteins Publishing Research Research Personnel Role S Phase Single-Stranded DNA Site Solid Neoplasm Test Result Testing Therapeutic Time Tumorigenicity cancer cell cancer therapy career chemotherapy chromosome missegregation effective therapy faculty research inhibitor/antagonist malignant breast neoplasm mouse model neoplastic cell novel prevent recruit replication stress response segregation skills success targeted cancer therapy therapy resistant tumor tumor progression

项目摘要

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.

项目总结/文摘