Molecular Mechanisms Controlling KIR Genes in NK Cells

描述（由申请人提供）：自然杀伤（NK）细胞使用杀伤细胞免疫球蛋白样受体（KIR）来区分正常细胞与感染细胞和恶性细胞。NK细胞表达KIR基因的明显随机分类。我们的长远目标是利用NK细胞治疗癌症和传染病。我们目前的目的是确定发育中的NK细胞如何启动并维持选择性KIR基因表达。在强有力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基因表达。这项拟议研究的基本原理是，了解KIR基因调控可能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。这项拟议中的研究是两所大学的研究人员合作进行的。首席研究员在NK细胞、HLA I类分子的免疫识别和分子生物学方面有着良好的研究记录。其他研究人员在基因表达控制和人类NK细胞发育方面处于领先地位。这种合作将产生一种协同效应，这是单个研究者难以企及的。我们的具体目标是：检测KIR基因表达调控的分子机制。2. 定义控制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细胞如何启动选择性KIR基因表达。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的研究技术来严格检验我们的假设。我们的期望是：1)我们将对NK细胞如何保持稳定的KIR表达有一个清晰的认识；2)我们将定义调节KIR转录的几个重要的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基因表达。我们的结果将是非常重要的，因为它们对于理解NK细胞如何区分正常细胞和异常细胞至关重要。更广泛的意义是，阐明KIR基因表达控制将为发育过程中的基因选择提供重要模型，并为出生缺陷和癌症提供见解。

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.