The Role of CD4+ T Cells in Oncogene Addiction

CD4 T 细胞在癌基因成瘾中的作用

• 批准号: 8525665
• 负责人: Stephanie Catherine Casey
• 金额: $ 4.92万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-16 至 2015-05-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8525665
• 关键词: Acute T Cell Leukemia; Antigen-Presenting Cells; Apoptosis; B-Lymphocytes; BCL2 gene; CD4 Positive T Lymphocytes; Cancer Biology; Cancer Patient; Cancerous; Cell Adhesion Molecules; Cell Aging; Cell Line; Cell Separation; Cells; Clinic; Clinical; Development; Flow Cytometry; Future; Gene Expression; Genes; Goals; Homing; Human; Immune; Immune system; In Vitro; Inflammation; Laboratories; Laboratory Study; Lead; Lymphoma; Malignant Neoplasms; Mediating; Medical Oncologist; Medicine; Memory; Mutate; Normal Cell; Oncogenes; Outcome; Patients; Primary Cell Cultures; Proteins; Recruitment Activity; Regulation; Research; Research Personnel; Research Proposals; Role; Signal Transduction; Specimen; System; T-Cell Activation; T-Lymphocyte; Techniques; Testing; Tetanus Helper Peptide; Thrombospondin 1; Transgenic Mice; Translational Research; Universities; Viral Tumor Antigens; Work; angiogenesis; base; bcr-abl Fusion Proteins; cancer therapy; career; design; human subject; imaging modality; improved; insight; leukemia/lymphoma; mouse model; novel; oncogene addiction; oncology; programs; protein expression; public health relevance; research study; self-renewal; senescence; therapeutic target; tool; training project; tumor; tumor growth; tumor microenvironment; tumorigenesis

DESCRIPTION (provided by applicant): A postdoctoral project is proposed by Stephanie C. Casey at the Department of Medicine, Division of Oncology at Stanford University under the sponsor Dr. Dean Felsher. This project will help understand how the immune system contributes to tumors caused by oncogenes. The Felsher laboratory studies how oncogenes initiate and maintain tumorigenesis. Oncogenes are genes that, when mutated, have the potential to turn a normal cell into a cancerous cell. Our laboratory utilizes the Tet-system to generate transgenic mouse models to modulate expression of select genes, such as the oncogene MYC (one of the most commonly dysregulated genes in human cancer), as well as other oncogenes such as RAS, BCR-ABL, and BCL2, both independently and cooperatively. We have found oncogene inactivation elicits dramatic tumor regression, and we have shown that a functioning immune system is essential to elicit oncogene addiction. During the proposed training, this project will elucidate how CD4+ T cells, an immune cell previously demonstrated by the Felsher laboratory to be crucial for sustained tumor regression, contribute to the tumor microenvironment. The project will test whether these CD4+ T cells express anti-angiogenic Thrombospondin-1 (TSP-1), assist in the development of senescence, and recruit B cells to generate anti-tumor memory. The Felsher lab's specialized transgenic mouse tools allow for an exceptional approach to examine oncogene signaling in the context of tumor microenvironment. The anticipated outcome of this project is an increased understanding of how parts of the adaptive immune system may be targeted alongside oncogenes to treat cancer. Future experiments may validate our results in human patients. The impact of this work may have implications for novel "druggable" therapeutic targets and will assist in the development of new cancer treatments. This research will help broaden the current understanding of how the immune system contributes to tumor growth and tumor regression. Furthermore, the findings from this study may provide insight as to the potential use of TSP-1 as an anti-cancer therapy. The applicant is highly motivated and aims to pursue an academic research career as an independent investigator in the field of cancer biology. The applicant has designed specific experiments to test targeted hypotheses using novel transgenic mouse models. Techniques such as mouse models, culture of primary cells and cell lines, flow cytometry and cell sorting, gene and protein expression studies, multi-parameter imaging modalities, and in vitro studies will be used. !

简介（由申请人提供）：斯坦福大学肿瘤学部医学系Stephanie C. Casey提出博士后项目，资助人Dean Felsher博士。这个项目将有助于了解免疫系统是如何导致致癌基因引起的肿瘤的。Felsher实验室研究癌基因如何启动和维持肿瘤发生。致癌基因是一种基因，当发生突变时，有可能使正常细胞变成癌细胞。我们的实验室利用tet系统生成转基因小鼠模型来调节选择基因的表达，如癌基因MYC（人类癌症中最常见的失调基因之一），以及其他癌基因如RAS， BCR-ABL和BCL2，无论是独立的还是合作的。我们已经发现癌基因失活会引起肿瘤的急剧消退，并且我们已经表明，一个功能正常的免疫系统对于引发癌基因成瘾是必不可少的。在拟议的培训期间，该项目将阐明CD4+ T细胞是如何促进肿瘤微环境的，CD4+ T细胞是Felsher实验室先前证明的对肿瘤持续消退至关重要的免疫细胞。该项目将测试这些CD4+ T细胞是否表达抗血管生成血栓反应蛋白-1 (TSP-1)，协助衰老的发展，并招募B细胞产生抗肿瘤记忆。Felsher实验室专门的转基因小鼠工具允许一种特殊的方法来检查肿瘤微环境背景下的癌基因信号。该项目的预期结果是增加对适应性免疫系统部分如何与癌基因一起靶向治疗癌症的理解。未来的实验可能会在人类患者身上验证我们的结果。这项工作的影响可能会对新的“可药物”治疗靶点产生影响，并将有助于开发新的癌症治疗方法。这项研究将有助于扩大目前对免疫系统如何促进肿瘤生长和肿瘤消退的理解。此外，本研究的发现可能为TSP-1作为抗癌治疗的潜在用途提供见解。申请人积极主动，希望在癌症生物学领域作为独立研究者从事学术研究。申请人设计了特定的实验来测试使用新型转基因小鼠模型的目标假设。将使用小鼠模型、原代细胞和细胞系培养、流式细胞术和细胞分选、基因和蛋白质表达研究、多参数成像模式以及体外研究等技术。！