Defining genetic pathways of plasma-cell neoplasia

定义浆细胞肿瘤的遗传途径

• 批准号: 8677776
• 负责人: Siegfried Janz
• 金额: $ 29.48万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-19 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8677776
• 关键词: Address; Applications Grants; Basic Science; Biochemical; Bioinformatics; Biological; Cataloging; Catalogs; Cells; Cessation of life; Complement; Event; Genes; Genetic; Genetic Screening; Genomics; Germinal Center B-Lymphocyte; Goals; Hematologic Neoplasms; Human; Lead; Malignant - descriptor; Malignant Neoplasms; Maps; Methods; Mission; Modeling; Molecular Genetics; Moloney Leukemia Virus; Multiple Myeloma; Mus; Mutagenesis; Neoplasms; Neoplastic Plasma Cell; Orthologous Gene; Outcome; Pathway interactions; Pattern; Phase; Phenotype; Plasma Cell Neoplasm; Plasma Cells; Plasmacytoma; Prevention; Prevention therapy; Preventive; Research; Research Project Grants; Retroviridae; Role; Screening for cancer; Site; Sleeping Beauty; Staging; System; Testing; TimeLine; Transgenes; Transgenic Mice; Transgenic Organisms; Translating; Transposase; United States; Validation; Virus; Work; activation-induced cytidine deaminase; anticancer research; base; cancer genetics; cancer prevention; cancer therapy; cell transformation; flexibility; follow-up; gene discovery; improved; innovation; insight; mouse model; new therapeutic target; novel; plasma cell development; prevent; programs; screening; sound; tool; tumor; tumor progression

DESCRIPTION (provided by applicant): Despite recent progress in cancer research, the ability to treat and prevent plasma-cell (PC) myeloma, the second most common hematologic cancer in the United States, remains severely limited. Addressing the current limitations will require additional research efforts, including projects that will lead to an enhanced understanding of the genetic pathways underlying malignant PC transformation. The long-term goal of this research program is to improve the outcome of myeloma and related PC neoplasms. The main objective of the proposed research, which represents an important step towards attaining the long-term goal, is to gain insight into the genetic pathways that drive PC transformation. Our central hypothesis is that unbiased genetic forward screening in mice that are genetically prone to PC malignancy will uncover candidate cancer driver genes that can be evaluated across the mouse-human species barrier in order to detect and validate orthologous driver genes in human PC tumors. Three specific research aims are proposed to test the central hypothesis and achieve the main objective of this application. Aims 1 and 2 are concerned with identifying candidate cancer driver genes in retrovirus- and transposon-based cancer screens in the iMyc?E¿ transgenic mouse, a gene-insertion model of the Myc-activating T(12;15) translocation in mouse plasmacytoma. Aim 3 is devoted to validating the newly discovered driver genes, including the involvement of their human orthologs in human PC tumors. The studies in Aim 1 will rely on a modified Moloney murine leukemia virus, MOL4070LTR. The studies in Aim 2 will take advantage of a double-transgenic Sleeping Beauty (SB) somatic mutagenesis system that uses the inducible transposase, SB11, to unleash the mutagenic transposon, T2/Onc2, in PCs. The studies in Aim 3 will first employ bioinformatics tools for gene validation, and then follow up with biochemical, molecular genetic and biological methods to assess the potential of selected driver genes as new targets for cancer therapy and prevention. Supported by strong preliminary results that provide a sound rationale for this application, the proposed research is poised to facilitate novel targeted approaches to the therapy and prevention of PC neoplasia.

描述（由申请人提供）：尽管癌症研究最近取得了进展，但治疗和预防浆细胞（PC）骨髓瘤（美国第二大常见血液癌症）的能力仍然受到严重限制。解决当前的局限性需要额外的研究工作，包括加深对恶性 PC 转化的遗传途径的了解的项目。该研究项目的长期目标是改善骨髓瘤和相关 PC 肿瘤的治疗结果。拟议研究的主要目标是深入了解驱动 PC 转化的遗传途径，这是实现长期目标的重要一步。我们的中心假设是，对遗传上易患 PC 恶性肿瘤的小鼠进行无偏见的基因正向筛查将发现候选癌症驱动基因，这些基因可以跨越小鼠-人类物种障碍进行评估，以便检测和验证人类 PC 肿瘤中的直系同源驱动基因。提出了三个具体的研究目标来检验中心假设并实现本申请的主要目标。目标 1 和 2 涉及在 iMyc?E 转基因小鼠中基于逆转录病毒和转座子的癌症筛选中鉴定候选癌症驱动基因，iMyc?E 转基因小鼠是小鼠浆细胞瘤中 Myc 激活 T(12;15) 易位的基因插入模型。目标 3 致力于验证新发现的驱动基因，包括其人类直系同源基因在人类 PC 肿瘤中的参与。目标 1 的研究将依赖于改良的莫洛尼鼠白血病病毒 MOL4070LTR。 Aim 2 中的研究将利用双转基因睡美人 (SB) 体细胞诱变系统，该系统使用诱导型转座酶 SB11 在 PC 中释放诱变转座子 T2/Onc2。目标3的研究将首先利用生物信息学工具进行基因验证，然后采用生物化学、分子遗传学和生物学方法来评估选定驱动基因作为癌症治疗和预防新靶点的潜力。强有力的初步结果为该应用提供了合理的理论依据，拟议的研究有望促进治疗和预防 PC 肿瘤的新的靶向方法。