Molecular Mechanisms Controlling KIR Genes in NK Cells

NK 细胞中控制 KIR 基因的分子机制

• 批准号: 6575509
• 负责人: Charles T. Lutz
• 金额: $ 18.1万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6575509
• 关键词: antibody receptor; biological signal transduction; clinical research; flow cytometry; gel mobility shift assay; gene expression; gene induction /repression; genetic promoter element; genetic regulatory element; human subject; immunoprecipitation; infection; methylation; molecular genetics; molecular shape; natural killer cells; neoplasm /cancer immunotherapy; nucleic acid probes; polymerase chain reaction; regulatory gene; tissue /cell culture

DESCRIPTION (provided by applicant): Natural killer (NK) cells use killer cell immunoglobulin-like receptors (KIR) to distinguish normal cells from infected and malignant cells. NK cells express an apparently random assortment of KIR genes. Our LONG RANGE GOAL is to use NK cells to treat cancer and infectious diseases. Our CURRENT OBJECTIVE is to identify how developing NK cells initiate and then maintain selective KIR gene expression. Supported by strong preliminary data, our CENTRAL HYPOTHESIS is that promoter methylation controls locus-specific and allele-specific KIR gene expression. The RATIONALE for the proposed research is that understanding KIR gene regulation could lead to effective immunotherapy of cancer and infectious diseases. Furthermore, our research will test the central paradigm of tissue-specific gene expression. The proposed research is a COLLABORATION between investigators at two universities. The principal investigator has an established record of research in NK ceils, immune recognition of HLA class I molecules, and molecular biology. The other investigators are leaders in gene expression control and in human NK cell development. The collaboration will produce a synergistic effect that is not easily matched by a single investigator. Our SPECIFIC AIMS are to 1. Test the molecular mechanisms of KIR gene expression control. 2. Define cis acting elements and trans-acting factors that control KIR gene expression. 3. Elucidate how developing NK cells initiate selective KIR gene expression. Our approach is INNOVATIVE. We have produced unique new data and we will combine several cutting-edge research techniques to rigorously test our hypotheses. It is our EXPECTATION that 1) we will develop a clear understanding of how NK cells maintain stable KIR expression; 2) we will define several important cis-acting elements and trans-acting factors that regulate KIR transcription; 3) we will identify what signals developing NK cells use to initiate KIR gene expression. Our results will be highly SIGNFICANT, because they will be essential for understanding how NK cells distinguish normal from aberrant cells. Of broader significance, elucidation of KIR gene expression control will provide an important model for gene choice in development and offer insights into birth defects and cancer.

描述(申请人提供)：自然杀伤(NK)细胞使用杀伤细胞免疫球蛋白样受体(KIR)来区分正常细胞、感染细胞和恶性细胞。NK细胞表达明显随机的KIR基因。我们的长期目标是使用NK细胞治疗癌症和传染病。我们目前的目标是确定发育中的NK细胞如何启动并维持KIR基因的选择性表达。在强大的初步数据的支持下，我们的中心假设是启动子甲基化控制着位点特异性和等位基因特异性的KIR基因的表达。提出这项研究的理由是，了解KIR基因的调控可以导致癌症和传染病的有效免疫治疗。此外，我们的研究将测试组织特异性基因表达的中心范式。这项拟议的研究是两所大学的研究人员合作进行的。这位首席研究员在自然杀伤细胞、人类白细胞抗原I类分子的免疫识别和分子生物学方面都有既定的研究记录。其他研究人员在基因表达控制和人类NK细胞开发方面处于领先地位。这种合作将产生一种单一研究人员难以比拟的协同效应。我们的具体目标是：1.检测KIR基因表达调控的分子机制。2.确定控制KIR基因表达的顺式作用元件和反式作用因子。3.阐明发育中的NK细胞如何启动KIR基因的选择性表达。我们的方法是创新的。我们已经产生了独特的新数据，我们将结合几种尖端研究技术来严格测试我们的假设。我们的期望是：1)我们将清楚地了解NK细胞如何维持稳定的KIR表达；2)我们将定义几个调节KIR转录的重要顺式作用元件和反式作用因子；3)我们将确定发育中的NK细胞使用什么信号来启动KIR基因的表达。我们的结果将是非常有意义的，因为它们将是理解NK细胞如何区分正常和异常细胞的关键。阐明KIR基因的表达调控将为发育过程中的基因选择提供一个重要的模型，并为研究出生缺陷和癌症提供更广泛的意义。