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）：我的长期目标是让自己成为顶级研究机构的独立科学家，研究在发育和癌症过程中调节细胞形态发生运动的基因调控网络（GRN）。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法方面的培训，补充了我之前在细胞和发育生物学技术方面的研究。 GRN 涵盖转录因子 (TF) 之间以及 TF 与其驱动特定细胞生物过程的靶基因之间的物理和调控关系。尽管它们在调节细胞侵袭行为中很重要，但转录因子及其指定侵袭性的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和免疫监视过程中细胞分散和器官形成的潜在机制，并且在癌症转移过程中受到错误调节。杜克大学舍伍德实验室建立了一个简单的体内模型，该模型独特地将强大的遗传、功能基因组和单细胞视觉分析结合在一起，对秀丽隐杆线虫幼虫发育过程中锚细胞 (AC) 通过 BM 侵入外阴上皮进行分析。我们目前对 AC 入侵的理解包括识别三个 TF 和一些假定的下游目标，这些目标既调节专门的侵入膜的建立，又调节 AC 在入侵期间去除 BM 的能力。在该奖项的指导阶段拟议的实验将开始通过 BM 表征 GRN 细胞入侵的特征，方法是 1) 识别 bZIP 癌基因 TF、fos-1a 的结合伴侣，以及 C 内 FOS-1A 结合位点的身份。线虫基因组； 2) 鉴定调节 AC 侵袭的其他 TF，并测试它们在体外调节癌细胞侵袭方面是否表现出保守功能。通过高级课程、参加全国会议、与 Marian Walhout 博士实验室（马萨诸塞大学医学院）的合作以及主任 Philip Benfey 博士的共同指导，功能基因组技术和系统生物学方法的培训将得到加速杜克大学系统生物学小组和基因组科学与政策研究所 (IGSP) 的教授。人类癌症体外检测培训将在 Stephen Weiss 博士（密歇根大学）的实验室进行。这些培训经验和指导阶段获得的数据将为开展独立研究生涯奠定基础。在该奖项的无指导阶段提出的研究包括 1) 表征包含 TF 结合位点的基因组调控区域，这些位点在入侵过程中控制 AC 中的基因表达；2) 确定对重演而言必要且充分的 TF 核心补充正常发育和人类癌症侵袭中的侵袭程序。公共健康相关性：细胞侵袭不仅是正常发育期间（例如血管生长和怀孕）期间的基本细胞生物学过程，而且是驱动人类转移性癌症扩散的潜在机制。确定参与促进线虫和人类癌症细胞侵袭的核心基因将有助于识别新的治疗靶点，以阻止与癌症相关的致死性。