QTL mapping for genes regulating apoptosis capacity

调控细胞凋亡能力基因的QTL定位

• 批准号: 7473113
• 负责人: Jianfeng Xu
• 金额: $ 22.28万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7473113
• 关键词: Ablation; Accounting; Affect; Alleles; Androgens; Animal Experiments; Animal Model; Apoptosis; Apoptosis Promoter; Applications Grants; BCL-2 Protein; Biological; Biological Assay; Biological Process; Cancer Family; Cancer Patient; Candidate Disease Gene; Case-Control Studies; Caspase; Cell Death; Cells; Characteristics; Chromosome Mapping; Collection; Complement; Complex; Data; Data Set; Development; Diagnosis; Disease; Dissection; Etiology; Etoposide; Evaluation; Event; Family; Frequencies; General Population; Genes; Genetic; Genetic Databases; Genetic Predisposition to Disease; Genetic Variation; Genome; Genotype; Goals; Guidelines; Haplotypes; Heritability; Heterozygote; High-Risk Cancer; Homozygote; Human; In Vitro; Individual; Induction of Apoptosis; Inflammatory; Inherited; International; Joints; Knock-out; Localized; Location; Lod Score; Malignant Neoplasms; Malignant neoplasm of prostate; Maps; Measures; Messenger RNA; Microsatellite Repeats; Minor; Molecular; Mutation; Nature; Numbers; Oncogenes; Outcome; Patients; Personal Satisfaction; Phenotype; Physiological Processes; Platelet Factor 4; Play; Polymerase Chain Reaction; Population; Population Study; Positioning Attribute; Predisposition; Principal Investigator; Process; Proliferating; Prostate; Proteins; Quantitative Trait Loci; Range; Rate; Regulation; Research Design; Research Personnel; Resolution; Risk; Risk Factors; Role; Signal Transduction; Signaling Protein; Staging; TP53 gene; Testing; Time; Tissues; Variant; Western Blotting; anticancer research; base; cancer genetics; cancer therapy; cancer type; carcinogenesis; case control; cell type; clinically significant; established cell line; follow-up; genetic linkage analysis; genetic risk factor; genetic variant; genome wide association study; genome-wide analysis; genome-wide linkage; human disease; improved; lymphoblastoid cell line; mRNA Expression; mouse model; neoplastic cell; novel; outcome forecast; programs; protein protein interaction; research study; self-renewal; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Apoptosis is a highly conserved, continuous physiological process for non-inflammatory cell death, and the dysregulation of apoptosis has been shown to contribute to the initiation and progression of the tumorigenesis process. Variations in apoptosis capacity are expected to influence an individual's risk and progression of cancers, and an improved understanding of the variation in apoptosis capacity between individuals is likely to be beneficial in the prognosis and treatment of various diseases. However, apoptosis is a complex process that involves hundreds of proteins and is composed of multiple levels of redundancy, which makes it is difficult and tedious to dissect the major players that determine apoptosis capacity at the molecular level by in vitro experiments and animal models. Here we propose an alternative approach to pinpoint the major determinants of apoptosis through the identification of quantitative trait loci (QTL) that determine apoptosis capacity using a linkage analysis in a collection of informative families. These apoptosis QTL will then be followed up by a positional candidate gene approach that focuses only on the functionally relevant genes in the target chromosomal regions, thus quickly narrowing down the search to genes that contribute to variations in apoptosis capacity and are most directly relevant to human diseases in the general population. In this grant application, we propose to investigate the genetic variations and determinants of apoptosis capacity, using a large collection of 188 hereditary prostate cancer (HPC) families. Using an existing genome-wide scan marker dataset, we can systematically identify chromosomal regions likely to contain genes responsible for determining individuals' apoptosis capacity, in contrast to subjective selection of specific genes for evaluation. Furthermore, we can compare the results from genome-wide screens for apoptosis capacity with the results from our previous genome-wide screens for hereditary prostate cancer, clinically significant prostate cancer, and all types of cancers to identify apoptosis genes that have the greatest impact on cancer susceptibility. Our proposal describes a novel and efficient approach to identify apoptosis genes that are critical in cancer susceptibility.

描述（由申请人提供）：细胞凋亡是一种高度保守、连续的非炎症性细胞死亡的生理过程，并且细胞凋亡的失调已被证明有助于肿瘤发生过程的启动和进展。细胞凋亡能力的变化预计会影响个体的癌症风险和进展，并且更好地了解个体之间细胞凋亡能力的变化可能有益于各种疾病的预后和治疗。然而，细胞凋亡是一个复杂的过程，涉及数百种蛋白质，由多级冗余组成，这使得通过体外实验和动物模型在分子水平上剖析决定细胞凋亡能力的主要参与者变得困难和繁琐。在这里，我们提出了一种替代方法，通过鉴定数量性状基因座（QTL）来查明细胞凋亡的主要决定因素，该基因座使用信息家族集合中的连锁分析来确定细胞凋亡能力。然后，通过位置候选基因方法跟踪这些凋亡 QTL，该方法仅关注目标染色体区域中功能相关的基因，从而快速将搜索范围缩小到导致凋亡能力变化且与普通人群中的人类疾病最直接相关的基因。在本次拨款申请中，我们建议利用 188 个遗传性前列腺癌 (HPC) 家族的大量数据来研究遗传变异和细胞凋亡能力的决定因素。使用现有的全基因组扫描标记数据集，我们可以系统地识别可能包含负责确定个体凋亡能力的基因的染色体区域，而不是主观选择特定基因进行评估。此外，我们可以将细胞凋亡能力的全基因组筛选结果与之前的遗传性前列腺癌、临床意义前列腺癌和所有类型的癌症全基因组筛选结果进行比较，以确定对癌症易感性影响最大的细胞凋亡基因。我们的提案描述了一种新颖有效的方法来识别对癌症易感性至关重要的细胞凋亡基因。