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（由适用提供）：尽管癌症研究最近进展，但在美国第二常见的血液学癌症治疗和预防血浆细胞（PC）骨髓瘤的能力仍然受到严重限制。解决当前的局限性将需要其他研究工作，包括将导致对恶性PC转化的遗传途径的理解增强的项目。该研究计划的长期目标是改善骨髓瘤和相关PC肿瘤的结果。拟议研究的主要目标是实现长期目标的重要一步，是洞悉推动PC转化的遗传途径。我们的中心假设是，在遗传上容易出现PC恶性肿瘤的小鼠中公正的遗传前进筛查将发现可以在小鼠人类物种屏障中进行评估的候选癌症驱动基因，以检测和验证人类PC肿瘤中的正交驱动基因。提出了三个特定的研究目的来检验中心假设并实现该应用的主要目标。 AIM 1和2与鉴定逆转录病毒和转座子的癌症筛查中的候选癌症驱动基因在IMYC？e e e trgenic小鼠中，这是MyC激活T（12; 15）小鼠浆细胞瘤中MyC激活T（12; 15）易位的基因插入模型。 AIM 3致力于验证新发现的驱动基因，包括其人类直系同源物在人类PC肿瘤中的参与。 AIM 1中的研究将依赖于改良的Moloney鼠白血病病毒Mol4070ltr。 AIM 2中的研究将利用双重转基因睡美（SB）体细胞诱变系统，该系统使用诱导型转座酶SB11在PC中释放诱变的转座子T2/ONC2。 AIM 3中的研究将首先采用生物信息学工具进行基因验证，然后跟进生化，分子遗传和生物学方法，以评估所选驱动基因作为癌症治疗和预防的新靶标的潜力。在强大的初步结果的支持下，为该应用提供了声音原理，拟议的研究被毒死，以促进针对PC肿瘤治疗和预防PC肿瘤的新型靶向方法。