Science Leadership and Integration

描述(由申请者提供)：该项目将利用小鼠遗传学来测试为人类癌症实施个性化药物所需的概念和方法。这将需要在人类癌症联盟(MMHCC)的小鼠模型内以及与NCI资助的其他组织一起，对遗传背景和基因表达网络在癌症易感性、进展和治疗反应中的系统遗传学分析进行联合研究。基于系统的方法的价值已经从对肥胖和糖尿病易感性的小鼠研究中得到证明，在这些研究中，正常组织中的基因表达网络揭示了反映潜在易感性的信号通路，以及作为可行治疗靶点的信号枢纽。对皮肤癌小鼠模型的类似研究已经确定了控制组织结构和功能的分级网络，并为导致皮肤癌易感性的机制提供了新的见解。这些综合系统方法在癌症方面的应用对MMHC正在进行的所有研究领域都有重大影响。该项目将包括一个核心项目，其目的是构建一个可浏览的数据库，其中包括来自种间回交小鼠和合作杂交RL系组织的组合单核苷酸多态(SNPs)和基因表达数据。这样的数据库对于癌症易感性和耐药性集群中的群体，以及更普遍的MMCC和其他NCI资助机构来说，都将是无价的。来自相同动物的组织库将提供给MMCC的成员，用于在蛋白质水平上研究基因表达的遗传控制。将在癌症敏感性和耐药性主题范围内设立试点项目，利用代表人类癌症主要形式的不同小鼠模型，使用相同的遗传方法来研究肿瘤敏感性。另一个目标是研究生殖系多态和躯体事件在癌症检测、进展和治疗反应中的相互作用。这些目标与路线图倡议有很大的重叠，特别是与综合癌症生物学计划(ICBP)、卓越研究专门计划(SPORT)、早期发现研究网络(EDRN)和癌症家庭登记(CFR)的目标有很大重叠。每个项目的代表都为这种比较的老鼠-人类遗传方法提供了支持材料，以分析癌症易感性的多个方面。

DESCRIPTION (provided by applicant): This project will exploit mouse genetics to test the concepts and approaches that will be required to implement personalized medicine for human cancer. This will require joint studies, both within the mouse models of human cancer consortium (MMHCC) and together with other NCI-funded organizations, of systems genetics analysis of genetic background and gene expression networks in cancer susceptibility, progression and therapeutic responses. The value of systems-based approaches has been demonstrated from mouse studies of susceptibility to obesity and diabetes, in which the gene expression networks in normal tissues have revealed signaling pathways that reflect underlying susceptibility, as well as signaling hubs that are viable therapeutic targets. Similar studies of mouse models of skin cancer have identified hierarchical networks that control tissue structure and function, and provided novel insights into mechanisms that lead to skin tumor susceptibility. The application of these integrative systems approaches to cancer has major implications for all of the areas of research being pursued by the MMHCC. This project will include a Core Project, the purpose of which is to construct a browsable database of combined single nucleotide polymorphisms (SNPs) and gene expression data from tissues from interspecific backcross mice and from the Rl lines of the Collaborative Cross. Such a data base would be invaluable both for groups in the Cancer Susceptibility and Resistance cluster, but also more generally within the MMHCC and in other NCI-funded bodies. A tissue bank from the same animals will be available to members of the MMHCC for investigations of the genetic control of gene expression at the protein level. Pilot projects will be set up within the cancer susceptibility and resistance theme to use the same genetic approaches to investigate tumor susceptibility using different mouse models that represent the major forms of human cancer. A further goal is to investigate the interplay between germline polymorphisms and somatic events in cancer detection, progression and treatment responses. These aims overlap substantially with the Roadmap initiative, and in particular with the goals of the Integrated Cancer Biology Program (ICBP), the Specialized Programs of Research Excellence (SPORE) program, the Early Detection Research Network (EDRN) and the Cancer Family Registry (CFR). Representatives of each of these programs have provided supporting materials for this comparative mouse-human genetic approach to analysis of multiple aspects of cancer susceptibility.