HTLV-1 的增殖作用-猫眼课题宝

HTLV-1 的增殖作用

批准号：

9246436

负责人：

Lee Ratner

金额：

$15.86万

依托单位：

WASHINGTON UNIVERSITY

依托单位国家：

美国

项目类别：

财政年份：

1995

资助国家：

美国

项目状态：

已结题

起止时间：

1995-09-28 至 2020-03-31

来源：

https://reporter.nih.gov/project-details/9246436

关键词：

Address Adult T-Cell Leukemia/Lymphoma Animal Model Animals Antibiotics Apoptosis Area Binding Biological Assay Cell Line Cells Clinical Clinical Research Clinical Trials Clonality Code DNA-Binding Proteins Defect Development Diet Disease Dissection Doxycycline Etiology Family Future Gene Chips Gene Expression Gene Targeting Genes Genetic Goals Growth Hematopoietic Neoplasms Human Human T-lymphotropic virus 1 Immunodeficient Mouse In Vitro Individual Infection Link Lymphocyte Lymphoma Maintenance Malignant Neoplasms Methodology Microarray Analysis Modeling Molecular Molecular Biology Molecular Profiling Monitor Multiple Myeloma Mus Mutation Oncoproteins Pathogenesis Pathogenicity Pathway interactions Physiological Research Resistance Role Solid Neoplasm Taxes Techniques Therapeutic Therapeutic Trials Time Transgenic Mice Transgenic Model Transgenic Organisms Transplantation Tumor Cell Line Variant Viral Virus Virus Integration Work arm base cell transformation experimental study gene product humanized mouse immortalized cell in vivo innovation molecular targeted therapies mouse model mutant new therapeutic target novel oncology pre-clinical programs public health relevance reconstitution resistance mechanism small hairpin RNA targeted treatment tumor tumor progression tumorigenesis

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DESCRIPTION (provided by applicant): HTLV-1 is the etiological agent of adult T-cell leukemia lymphoma (ATLL). ATLL cells are characterized by constitutive NFκB activation, a key feature of other lymphomas, myeloma, and solid tumors. The Tax oncoprotein is the key viral determinant for NFκB activation. Our previous studies showed that the classical and especially, the alternative NFκB pathways were critical in conferring resistance to apoptosis. The current study will use innovative, physiological lymphoma models to define the role in tumorigenesis of each NFκB pathway and identify the key NFκB target gene responsible for these effects. Aim 1. Which NFκB pathway is critical for HTLV tumorigenesis in humanized mice? In this study, a new humanized mouse model is used for HTLV-1 infection and lymphoma development. We will use viral variants expressing Tax mutants with defects in activating the alternative NFκB pathway or both NFκB pathways, in order to define their role in disease pathogenesis. A novel high-throughput viral integration assay is used to monitor clonality of infected cells over the course o these experiments. Aim 2. Which NFκB targets are required for maintenance and progression of Tax transgenic tumors? In this study, a new inducible Tax transgenic mouse model of lymphoma is utilized to assess the role of specific NFκB target genes in tumor progression using microarray analysis. Aim 3. Which NFκB target genes are critical for HTLV transformation? In this study, shRNAs to NFκB1 (p105) and NFκB2 (p100) are used to assess each individual pathway. HTLV-1 transformed cells expressing one of both of these shRNAs will be subjected to microarray analysis to determine which pathway is responsible for activation of specific target genes. Moreover, their contribution of select NFκB target genes to resistance to apoptosis will be assessed. It is expected that the information these physiologically relevant mouse models will identify key target genes that may be inhibited in therapeutic trials of ATLL or other lymphomas.

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