Project 2: Characterizing the role of ATM and MSH2 in genome stability

项目 2：表征 ATM 和 MSH2 在基因组稳定性中的作用

• 批准号: 10260496
• 负责人: Bao Q Vuong
• 金额: $ 18.08万
• 依托单位: CITY COLLEGE OF NEW YORK
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-26 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10260496
• 关键词: ATM deficient; Affect; Antibodies; Antibody Formation; Antibody Repertoire; Applications Grants; B-Lymphocytes; Bacteria; Biological Models; Cancer Cell Growth; Cell Death; Cell Line; Cell Survival; Cells; Chromosomal translocation; Chromosome abnormality; Cities; Clustered Regularly Interspaced Short Palindromic Repeats; Code; Colorectal Cancer; Community Outreach; DNA; DNA Damage; DNA Mismatch Repair Protein MSH2; DNA Repair; DNA Repair Gene; DNA Repair Pathway; Data; Defect; Education and Outreach; Embryonic Development; Endometrial Carcinoma; Engineering; Funding; Future; Genes; Genetic Recombination; Genetically Engineered Mouse; Genome; Genome Stability; Genomic DNA; Growth; Immune system; Immunotherapy; Impairment; Lymphoma; MSH2 gene; Malignant Neoplasms; Memorial Sloan-Kettering Cancer Center; Methods; Molecular; Mus; Mutate; Mutation; New York; Normal Cell; Nucleotides; Oxides; Pathway interactions; Process; Proteins; Research; Research Personnel; Role; Students; Supervision; Therapeutic; Training; Transformed Cell Line; Underrepresented Minority; Vaccines; Virus; anticancer research; ataxia telangiectasia mutated protein; base; cancer cell; cancer predisposition; cell growth; cell killing; college; conditional knockout; experience; experimental study; genome integrity; improved; in vivo; inhibitor/antagonist; mouse development; novel; pathogen; prevent; recruit; response; small molecule inhibitor; tool; tumor; tumorigenesis; virtual

Cancer cells have mutations that alter when they will grow and die. The cells acquire these mutations through DNA damage. Normally, when a cell experiences DNA damage, DNA repair proteins are recruited to correct the damaged or mutated DNA. If the damage is not corrected, a cell death pathway is activated that kills the cell. However, mistakes in the DNA damage response can occur, resulting in the survival of cells with mutated DNA that can give rise to cancer. People who are born with mutations in genes involved in DNA repair are predisposed to developing cancer and many people not born with these mutations who develop cancer have been found to have acquired mutations in DNA repair genes in their tumors. To study how cells repair DNA damage, we use mouse B cells as a model system. To generate antibodies that recognize and eliminate pathogens, B cells are genetically programmed to mutate and delete antibody coding genes. The B cells carefully coordinate their DNA damage and DNA repair pathways to avoid triggering a cell death pathway. ATM (ataxia telangiectasia mutated) and MSH2 (MutS homologue 2) are proteins that are essential for two distinct DNA repair pathways. Mice engineered to lack either ATM or MSH2 display defects in antibody production and have a similar cancer predisposition as people born with mutations in these DNA repair genes. However, mice that lack both ATM and MSH2 are not viable (unpublished data). We hypothesize that the combined loss of ATM and MSH2 causes the accumulation of genomic DNA damage that prevents mouse development. We propose experiments to characterize the mechanism by which ATM and MSH2 cooperatively regulate genome stability and experiments to determine if these unique molecular pathways can be exploited therapeutically in cancer. The research will be led by Dr. Vuong and Dr. Chaudhuri at The City College of New York and Memorial Sloan-Kettering Cancer Center, respectively. Dr. Vuong, a former trainee of Dr. Chaudhuri, will supervise CCNY students in the proposed research, which will enhance the pipeline of underrepresented minorities trained in cancer research. The completion of the proposed research will improve the competitiveness of future grant applications from Dr. Vuong, who is a new investigator.

癌细胞有突变，改变他们何时生长和死亡。细胞通过以下途径获得这些突变： DNA损伤。通常，当细胞经历DNA损伤时，DNA修复蛋白被招募来纠正 受损或突变的DNA如果损伤得不到纠正，细胞死亡途径就会被激活， cell.然而，DNA损伤反应中的错误可能发生，导致突变的细胞存活。 可能导致癌症的DNA。与生俱来的DNA修复基因突变的人， 容易患上癌症，许多人出生时没有这些突变，但患上癌症， 在他们的肿瘤中发现了DNA修复基因的突变。研究细胞如何修复DNA 损伤，我们使用小鼠B细胞作为模型系统。产生抗体来识别并消除 在病原体中，B细胞被遗传编程以突变和删除抗体编码基因。B细胞 仔细协调它们的DNA损伤和DNA修复途径，以避免触发细胞死亡途径。 ATM（共济失调毛细血管扩张突变）和MSH 2（MutS同源物2）是两种必需的蛋白质， 不同的DNA修复途径缺乏ATM或MSH 2的小鼠在抗体中显示缺陷 这些DNA修复基因突变的人具有类似的癌症易感性。 然而，缺乏ATM和MSH 2的小鼠是不能存活的（未发表的数据）。我们假设 ATM和MSH 2的联合缺失导致基因组DNA损伤的积累， 发展我们提出了实验来表征ATM和MSH 2合作的机制， 调节基因组的稳定性和实验，以确定这些独特的分子途径是否可以利用 在癌症治疗上。这项研究将由纽约城市学院的Vuong博士和Chaudhuri博士领导。 约克和纪念斯隆-凯特琳癌症中心。Vuong博士曾是Chaudhuri博士的实习生， 将在拟议的研究中监督CCNY学生，这将增强代表性不足的人才管道 少数民族接受过癌症研究培训。拟议研究的完成将改善 Vuong博士是一名新的研究员，他的研究有助于提高未来赠款申请的竞争力。