Molecular Basis of Aneuploidy

非整倍体的分子基础

基本信息

批准号：
7818672
负责人：
DEBANANDA PATI
金额：
$ 45.95万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7818672
关键词：
12q 20 year old Address Adolescent Affect Anaphase Androgens Aneuploidy Animal Model Area Binding Sites Biological Assay Breast Breeding Cell Cycle Cell Line Cell Nucleus Cell Proliferation Cell division Cells Child Childhood Osteosarcoma Chromatids Chromosomal Instability Chromosomal Stability Chromosome Segregation Chromosome abnormality Chromosomes Chromosomes, Human, Pair 10 Chromosomes, Human, Pair 8 Cleaved cell Complex Computer Simulation Coupled Data Development Diagnosis Diagnostic Diploidy Disease Distal Ectopic Expression Elements Endopeptidases Engineering Enzymes Epithelial Cells Estrogens Event Femur Funding Gene Expression Generations Genes Genetic Genetic Crosses Genetically Engineered Mouse Genomics Germ-Line Mutation Growth Hematology Hormonal Hormones Human Human Characteristics Human Cloning In Vitro Inbred BALB C Mice Incidence Indium Initiator Codon Journals Knee Knockout Mice Lead Li-Fraumeni Syndrome Life Light Link Luciferases Malignant - descriptor Malignant Bone Neoplasm Malignant Childhood Neoplasm Malignant Neoplasms Mammary Neoplasms Mammary Tumorigenesis Mammary gland Manuscripts Measures Mediating Messenger RNA Metaphase Mitosis Mitotic Modeling Molecular Molecular Genetics Molecular Models Monosomy 17 Mus Mutation Nature Neoplasm Metastasis Normal Cell Normal tissue morphology Nuclear Occupations Oncogenes Osteoblasts Outcome Parents Pathway interactions Patients Peptide Hydrolases Phenotype Physiological Plasmids Play Pre-Clinical Model Preparation Primary Neoplasm Process Progesterone Promoter Regions Prostate Protein p53 Proteins Publications Published Comment Publishing Recovery Reporter Research Research Design Response Elements Risk Role Serum Set protein Signal Transduction Sister Chromatid Solid Neoplasm Starvation Steroids Syndrome System TP53 gene Technology Teenagers Testing Tetracyclines Therapeutic Intervention Transcriptional Regulation Transfection Transgenic Mice Transgenic Organisms Trisomy Tumor Suppressor Proteins United States National Academy of Sciences United States National Institutes of Health Validation Work base bone bone cell cancer type carcinogenesis cohesin cohesion cohort design experience fibula in vivo mRNA Expression malignant breast neoplasm molecular modeling mouse model novel oncology osteosarcoma overexpression parent grant parent project premature promoter public health relevance research study response segregation separase steroid hormone therapeutic target tibia tissue culture tool transcription factor tumor tumor initiation tumorigenesis vector

项目摘要

DESCRIPTION (provided by applicant): This proposal is in response to the Notice# NOT-OD-09-058, title: NIH announces the availability of Recovery Act Funds for Competitive Revision Applications. The broad aim of our parent grant (RO1 CA109330, "Molecular Basis of Aneuploidy") is to understand how aberrations in sister chromatid separation contribute to chromosomal missagregation and generation of aneuploidy. The purpose of the revised application is to examine the role of Separase overexpression and its mislocalization in osteosarcoma as a mechanism of aneuploidy development, and in the initiation and progression of osteogenic sarcomas. Unstable chromosome number known as aneuploidy is a hallmark of pediatric osteosarcoma. There currently is not an effective way to study this type of cancer, largely because there is no suitable animal model to investigate the mechanism of chromosomal instability in osteosarcoma. The revised application addresses a key question in osteosarcoma research and attempts to develop a new mouse model for aneuploid osteosarcoma. While tumor suppressor protein p53 and steroid hormones such as androgens have long been implicated in the development of osteosarcoma in adolescents, the precise mechanisms of their contribution are not well understood. Here we propose that Separase, an enzyme that is essential in chromosomal separation during cell division, works in conjunction with both mutations in p53 and with androgens to promote osteoblast (the cell that make growing bone) aneuploidy and osteosarcoma. To investigate this novel idea in an in vivo setting, we propose to develop and characterize genetically engineered mouse models. We plan to use murine genetic crosses to engineer molecular models that control gene expression in the mouse. The ability to combine genetic and physiological manipulations (e.g. hormone levels) will allow us to address the complex nature of osteosarcoma tumorigenesis, which is thought to be a multi-step process. The use of genomic technology will allow us to find commonalities between our mouse model(s) and human osteosarcoma. We are confident the current project will not only shed light on new mechanisms of aneuploidy contributing to osteosarcoma initiation and progression but will also provide a potential pre-clinical model that emulates several aspects of the human osteosarcoma. PUBLIC HEALTH RELEVANCE: The current project addresses a key question in osteosarcoma research that has not been addressed before and attempts to develop a new mouse model for aneuploid osteosarcoma. While tumor suppressor protein p53 and mitogenic hormones have long been implicated to play a role in osteosarcoma in adolescents, the precise mechanisms of their contributions are not well understood. Here we propose that the cohesin protease, Separase, a critical cell cycle regulating protein, works in conjunction with mutations in p53 coupled with mitogenic hormones in promoting osteoblast (the cell that make growing bone) aneuploidy and thus initiating osteosarcoma and fuelling its progression.

描述（由申请人提供）：本提案是对通知# NOT-OD-09-058 的回应，标题为：NIH 宣布为竞争性修订申请提供恢复法案基金。我们的母基金（RO1 CA109330，“非整倍体的分子基础”）的主要目标是了解姐妹染色单体分离中的畸变如何导致染色体错配和非整倍体的产生。修订后的申请的目的是检查分离酶过度表达及其在骨肉瘤中的错误定位作为非整倍性发育机制以及在成骨肉瘤的起始和进展中的作用。不稳定的染色体数量（称为非整倍体）是小儿骨肉瘤的一个标志。目前尚无有效的方法来研究此类癌症，很大程度上是因为没有合适的动物模型来研究骨肉瘤染色体不稳定的机制。修订后的申请解决了骨肉瘤研究中的一个关键问题，并试图开发一种新的非整倍体骨肉瘤小鼠模型。虽然肿瘤抑制蛋白 p53 和雄激素等类固醇激素长期以来一直与青少年骨肉瘤的发展有关，但其作用的确切机制尚不清楚。在这里，我们提出，分离酶（一种在细胞分裂过程中染色体分离中必不可少的酶）与 p53 突变和雄激素一起作用，促进成骨细胞（产生骨骼的细胞）非整倍体和骨肉瘤。为了在体内研究这一新想法，我们建议开发并表征基因工程小鼠模型。我们计划利用小鼠遗传杂交来设计控制小鼠基因表达的分子模型。结合遗传和生理操作（例如激素水平）的能力将使我们能够解决骨肉瘤肿瘤发生的复杂性质，这被认为是一个多步骤的过程。基因组技术的使用将使我们能够找到小鼠模型和人类骨肉瘤之间的共性。我们相信，当前的项目不仅将揭示导致骨肉瘤发生和进展的非整倍性的新机制，而且还将提供模拟人类骨肉瘤多个方面的潜在临床前模型。公共健康相关性：当前项目解决了骨肉瘤研究中以前未解决过的一个关键问题，并试图开发一种新的非整倍体骨肉瘤小鼠模型。虽然肿瘤抑制蛋白 p53 和促有丝分裂激素长期以来一直被认为在青少年骨肉瘤中发挥作用，但其作用的确切机制尚不清楚。在这里，我们提出，粘连蛋白分离酶（Separase）是一种关键的细胞周期调节蛋白，与 p53 突变以及促有丝分裂激素一起作用，促进成骨细胞（使骨骼生长的细胞）非整倍性，从而引发骨肉瘤并加速其进展。