Elucidating the Gene Regulatory Networks that Specify Invasive Behavior

阐明指定入侵行为的基因调控网络

基本信息

批准号：
8028801
负责人：
David Matus
金额：
$ 13.42万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-17 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8028801
关键词：
Architecture Automobile Driving Award Basement membrane Behavior Binding Binding Sites Biological Biological Process Blood Vessels C. elegans genome Caenorhabditis elegans Cancer Model Cells Cellular biology Collaborations Complement Complex Data Development Developmental Biology Dimerization Dissection Disseminated Malignant Neoplasm Elements Epithelium Excision Family member Fingers Gene Components Gene Expression Gene Targeting Genes Genetic Genome Genomics Goals Growth Homologous Gene Human Human Genome Hybrids Immunologic Surveillance In Vitro Institutes Institution Intervention Laboratories Malignant Epithelial Cell Malignant Neoplasms Massachusetts Membrane Mentors Mentorship Michigan Modeling Movement Neoplasm Metastasis Nucleic Acid Regulatory Sequences Organ Orthologous Gene Pathway Analysis Phase Phenotype Phylogenetic Analysis Pregnancy Process Property Proteins RNA Interference Regulation Regulator Genes Regulatory Element Research Research Proposals Resolution Role Science Policy Scientist Site Specific qualifier value Systems Biology Techniques Testing Time Training Transcription Factor AP-1 Transcription Factor Oncogene Universities Vertebrates Visual Work Yeasts anti-cancer therapeutic base career dimer expectation experience functional genomics in vitro Assay in vivo in vivo Model innovation insight jun Oncogene medical schools new therapeutic target novel strategies programs promoter research study symposium therapeutic target tool transcription factor

项目摘要

DESCRIPTION (provided by applicant): My long-term goal is to establish myself as an independent scientist at a top-tier research institution studying the gene regulatory networks (GRNs) that regulate cell morphogenetic movements during development and cancer. Towards this end, the proposed research advances my training in functional genomics and systems biology approaches that complement my previous research in cellular and developmental biology techniques. GRNs encompass both the physical and regulatory relationships amongst transcription factors (TFs) and between TFs and their target genes that drive specific cell biological processes. Despite their importance in regulating cell invasive behavior, the TFs and the identity of their downstream targets that specify invasiveness is largely unknown. Cell invasion through basement membrane (BM) serves as a mechanism underlying cell dispersal and organ formation during normal development, immune surveillance, and is mis-regulated during cancer metastasis. The Sherwood laboratory at Duke University has established a simple in vivo model that uniquely combines powerful genetic, functional genomic, and single cell visual analyses of anchor cell (AC) invasion through BM into the vulval epithelium during C. elegans larval development. Our current understanding of AC invasion includes the identification of three TFs and a handful of putative downstream targets that regulate both the establishment of a specialized invasive membrane and the ability of the AC to remove BM during invasion. The proposed experiments during the mentored phase of the award will begin to characterize the GRNs underlying cell invasion through BM by 1) identifying the binding partner of the bZIP oncogene TF, fos-1a, and the identity of FOS-1A binding sites within the C. elegans genome; and 2) identifying additional TFs that regulate AC invasion and testing whether they show conserved functions in regulating carcinoma cell invasion in vitro. Training in functional genomic techniques and systems biology approaches will be accelerated through advanced course work, attendance at national conferences, a collaboration with Dr. Marian Walhout's laboratory (University of Massachusetts Medical School), and co-mentorship by Dr. Philip Benfey, the director of Duke University's Systems Biology group and the Institute for Genome Sciences and Policy (IGSP). Training in human cancer in vitro assays will be carried out in the laboratory of Dr. Stephen Weiss (University of Michigan). These training experiences and the data acquired during the mentored phase will provide the basis to launch an independent research career. The research proposed in the unmentored phase of the award includes 1) characterizing the genomic regulatory regions that contain TF-binding sites that control gene expression in the AC during invasion and 2) determining the core complement of TFs that are both necessary and sufficient to recapitulate an invasion program in normal development and in human cancer invasion. PUBLIC HEALTH RELEVANCE: Cell invasion is not only a fundamental cell biological process during times of normal development (e.g., blood vessel growth and pregnancy), but is the underlying mechanism driving the spread of metastatic cancer in humans. Determining the core genes involved in promoting cell invasion in both C. elegans and human cancer will allow for the identification of new therapeutic targets to halt the lethality associated with cancer.

描述（由申请人提供）：我的长期目标是在研究基因调节网络（GRN）的顶级研究机构中确立自己的独立科学家，该基因调节网络（GRNS）调节发育和癌症期间细胞形态发生运动。为此，拟议的研究推进了我在功能基因组学和系统生物学方面的培训，以补充我先前在细胞和发育生物学技术方面的研究。 GRNS包括转录因子（TFS）之间以及TFS及其靶向基因之间的物理和调节关系，这些基因驱动了特定的细胞生物学过程。尽管它们在调节细胞侵入性行为方面的重要性，但指定侵入性的TF和其下游靶标的身份在很大程度上是未知的。通过基底膜（BM）的细胞侵袭是正常发育，免疫监测过程中细胞扩散和器官形成的一种机制，在癌症转移期间被错误调节。杜克大学的Sherwood实验室已经建立了一个简单的体内模型，该模型在秀丽隐杆线虫幼虫发育过程中通过BM侵袭了锚固细胞（AC）浸入BM进入外阴上皮的强大遗传，功能性基因组和单细胞视觉分析。我们目前对AC入侵的理解包括鉴定三个TF和少数推定的下游目标，这些目标既调节了专门的侵入性膜的建立，又是AC在入侵期间消除BM的能力。在奖励的指导阶段所提出的实验将开始表征通过BM通过BM侵袭的GRN，通过1）识别BZIP Oncogene TF，FOS-1A的结合伴侣，以及C. elegrans基因组中FOS-1A结合位点的身份； 2）确定调节AC侵袭的其他TF，并测试它们是否在调节体外调节癌细胞侵袭方面表现出保守的功能。功能基因组技术和系统生物学方法的培训将通过高级课程工作，参加国家会议，与玛丽安·沃尔霍特（Marian Walhout）博士的实验室（马萨诸塞州医学院）的合作以及杜克大学生物学集团和基因研究所主任菲利普·本菲（Philip Benfey）的合作来加速。斯蒂芬·魏斯（Stephen Weiss）（密歇根大学）的实验室将进行体外测定的人类癌症培训。这些培训经验和在指导阶段获得的数据将为启动独立研究职业提供基础。在奖励的未注册阶段提出的研究包括1）表征包含TF结合位点的基因组调节区域，这些调节区域在侵入期间控制基因表达的基因表达和2）确定TF的核心补体，这些TF的核心补体在正常发育和人类癌症的侵袭中既是必要且足以在正常发育和人类癌症入侵中概括入侵计划。公共卫生相关性：细胞侵袭不仅是正常发育时期（例如血管生长和妊娠）的基本细胞生物学过程，而且是推动转移性癌症传播的基本机制。确定促进秀丽隐杆线虫和人类癌症中促进细胞侵袭的核心基因将允许鉴定新的治疗靶标，以阻止与癌症相关的致死性。