Evolution of transmissible cancers and genetics of host resistance

传染性癌症的进化和宿主耐药性的遗传学

• 批准号: 9899956
• 负责人: Michael Jeffrey Metzger
• 金额: $ 19.3万
• 依托单位: PACIFIC NORTHWEST RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9899956
• 关键词: Animals; Bivalvia; Bromodeoxyuridine; CRISPR/Cas technology; Cancer Biology; Cancer Etiology; Cancer Model; Candidate Disease Gene; Cells; Chromium; Clams; Clinical; Cloning; Collaborations; DNA Transposable Elements; DNA copy number; Development; Diagnosis; Disease; Engraftment; European; Event; Evolution; Experimental Models; Exposure to; Genes; Genetic; Genetic Determinism; Genetic Polymorphism; Genome; Genomic Segment; Gills; Goals; Graft Rejection; Hemocytes; Hemolymph; Horizontal Disease Transmission; Host resistance; Human; Immune response; Individual; Infiltration; Injections; Integration Host Factors; Invertebrates; Investigation; Kinetics; Lead; Learning; Leukemic Cell; Location; Malignant - descriptor; Malignant Neoplasms; Mentorship; Methods; Microsatellite Repeats; Mitochondrial DNA; Modeling; Morbidity - disease rate; Mussels; Mutation; Neoplasm Metastasis; Neoplasms; Normal Cell; Oncogenes; Oncogenic; Oysters; Play; Population; Positioning Attribute; Predisposition; Process; Proto-Oncogenes; Reporting; Research; Resistance; Retroelements; Retrotransposon; Retroviral Vector; Retrovirology; Role; Route; Sampling; Seawater; Site; Steam; Structure; System; Testing; Training; United States National Institutes of Health; Universities; Variant; base; cancer cell; cancer genetics; feeding; genetic linkage analysis; integration site; leukemia; mortality; mouse model; neoplastic; neoplastic cell; pathogen; pressure; public health relevance; reference genome; tissue culture; transmission process; Animals; Bivalvia; Bromodeoxyuridine; CRISPR/Cas technology; Cancer Biology; Cancer Etiology; Cancer Model; Candidate Disease Gene; Cells; Chromium; Clams; Clinical; Cloning; Collaborations; DNA Transposable Elements; DNA copy number; Development; Diagnosis; Disease; Engraftment; European; Event; Evolution; Experimental Models; Exposure to; Genes; Genetic; Genetic Determinism; Genetic Polymorphism; Genome; Genomic Segment; Gills; Goals; Graft Rejection; Hemocytes; Hemolymph; Horizontal Disease Transmission; Host resistance; Human; Immune response; Individual; Infiltration; Injections; Integration Host Factors; Invertebrates; Investigation; Kinetics; Lead; Learning; Leukemic Cell; Location; Malignant - descriptor; Malignant Neoplasms; Mentorship; Methods; Microsatellite Repeats; Mitochondrial DNA; Modeling; Morbidity - disease rate; Mussels; Mutation; Neoplasm Metastasis; Neoplasms; Normal Cell; Oncogenes; Oncogenic; Oysters; Play; Population; Positioning Attribute; Predisposition; Process; Proto-Oncogenes; Reporting; Research; Resistance; Retroelements; Retrotransposon; Retroviral Vector; Retrovirology; Role; Route; Sampling; Seawater; Site; Steam; Structure; System; Testing; Training; United States National Institutes of Health; Universities; Variant; base; cancer cell; cancer genetics; feeding; genetic linkage analysis; integration site; leukemia; mortality; mouse model; neoplastic; neoplastic cell; pathogen; pressure; public health relevance; reference genome; tissue culture; transmission process

SUMMARY: Cancer is not a single event. It continues to evolve as is multiplies, spreads through its host, and evades its host’s basic mechanisms of recognition. We identified a retrotransposon, Steamer, amplified in a leukemia-like disease in soft-shell clams. Through investigation of integration sites of the Steamer retrotransposon, mtDNA SNPs, and polymorphic microsatellites, I discovered that the disease is spread by horizontal transmission of leukemic cells themselves, acting as a contagious cancer, and we have found that this is a widespread phenomenon in multiple bivalves. Based on my preliminary investigations while under the mentorship of Dr. Stephen Goff at Columbia University, I propose to investigate the evolution of transmissible cancers and the role of the retroelement, Steamer, in development of the disease as well as the mechanism of transmission of M. arenaria leukemia and the development of host resistance. This research will build on my previous training in retrovirology and cancer biology as I transition into independent academic research position where I will develop this cancer system as a unique model of leukemia. This will be done in three independent, but interconnected aims: (1) Investigate the mutations and selective pressures which drive cancer evolution including the role of the Steamer retrotransposon, (2) determine the route and mechanism of cancer cell transmission, and (3) identify the host genetic determinants of cancer cell engraftment/rejection. This unique invertebrate cancer model will allow us to learn more about cancer evolution and the role of retroelements in cancer, and to investigate leukemia acquisition and fundamental mechanisms of self/nonself recognition.

概括： 癌症不是一个事件。它继续演变，随着乘以繁殖，通过其宿主传播，并逃避 主机的基本认可机制。我们确定了逆转座子，蒸锅，在白血病样中放大 软壳蛤的疾病。通过研究蒸汽逆转座子的整合位点mtDNA SNP和多态微卫星，我发现该疾病是通过水平传播传播的 白血病细胞本身，充当传染性癌症，我们发现这是一个宽度 多个双壳类中的现象。根据我的初步调查，在博士的心态下。 哥伦比亚大学的斯蒂芬·高夫（Stephen Goff），我建议调查可传染性癌症和 追溯，蒸笼的作用在疾病发展中以及M的传播机理。 阿雷纳里亚白血病和宿主抵抗的发展。这项研究将基于我以前的培训 当我转变为独立的学术研究职位时，逆转录病毒学和癌症生物学 将这种癌症系统作为白血病的独特模型。这将在三个独立中完成，但是 相互联系的目的：（1）研究驱动癌症进化的突变和选择性压力 包括蒸锅逆转座子的作用，（2）确定癌细胞的路线和机理 传播和（3）确定癌细胞植入/排斥的宿主遗传决定剂。这个独特 无脊椎动物癌模型将使我们能够了解有关癌症进化的更多信息以及追溯元素在 癌症，并研究自我/非自然识别的白血病的获取和基本机制。