Molecular Mechanisms Controlling NK Receptors

控制 NK 受体的分子机制

• 批准号: 7729934
• 负责人: Charles T. Lutz
• 金额: $ 37.48万
• 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 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7729934
• 关键词: Address; Affect; Attention; Binding; CREB1 gene; Cancer Patient; Cataloging; Catalogs; Cells; Chromatin; Communicable Diseases; Complement component C1s; DNA; DNA Methylation; DNA-Directed RNA Polymerase; Development; Disease; Dysmyelopoietic Syndromes; Elements; Epigenetic Process; Future; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Goals; Health; Histone Deacetylase Inhibitor; Human; Immunity; Immunoglobulins; In Vitro; Individual; Interleukin-15; Interleukin-2; Killer Cells; Licensing; Lymphocyte; Lymphoma; Maintenance; Malignant Neoplasms; Messenger RNA; Methylation; Molecular; Mus; NK Cell Activation; Natural Immunity; Natural Killer Cells; Non-Malignant; Patients; Pattern; Pharmaceutical Preparations; Physiology; Polymerase; Production; Public Health; Reagent; Receptor Cell; Receptor Gene; Regulation; Research; Research Personnel; Testing; Text; Time; Work; base; cancer cell; cancer immunotherapy; cancer therapy; cell killing; chemokine; cooperative study; cytokine; cytotoxic; cytotoxicity; effective therapy; health application; human disease; in vivo; promoter; public health relevance; receptor; receptor expression; transcription factor

DESCRIPTION (provided by applicant): Natural killer (NK) cells kill infected and malignant cells and direct subsequent adaptive immunity. NK cells distinguish normal from aberrant cells largely via killer cell immunoglobulin-like receptors (KIR). Despite high homology between KIR genes, individual NK cells express distinct numbers and combinations of clonally-restricted KIR (crKIR) genes. In contrast to crKIR, KIR2DL4 is expressed by all NK cells, preceding crKIR expression during NK development. The long-range goal is to use NK cells as effective treatments of cancer and infectious diseases. As the next logical step toward that goal, the current objectives are to further characterize KIR expression control in normal physiology and during epigenetic therapy of lymphoma and myelodysplastic syndrome. The rationale for the proposed research is that once KIR gene regulation is better understood, then KIR expression can be manipulated to make effective NK cells reagents in immunotherapy of cancer and infectious diseases. In this proposal, 2DL4 and crKIR promoters will be investigated, with special attention to mechanisms that overcome DNA methylation and repressive chromatin. Because so little is known about how lymphocyte-specific gene expression is influenced by cancer and by epigenetic therapy, we will study how DNA methylation and histone deacetylase inhibitor drugs affect KIR promoter methylation, KIR expression, and NK cell activation in myelodysplastic syndrome and lymphoma patients. This work may explain why NK function is poor in cancer patients and might suggest strategies for boosting immunity in these patients. We will catalog NK cell microRNA expression and their target mRNAs and we will investigate the microRNA mechanisms that regulate "dangerous" cytotoxic NK cells and "unlicensed" inhibitory receptor- negative NK cells. This will provide the basic information needed for future studies on control of NK developmental decisions in health and disease. This study will 1) develop a clear understanding of the multiple layers of regulation that control the initiation and maintenance of KIR expression; 2) establish for the first time how epigenetic therapy affects nonmalignant human lymphocyte gene expression and function in vivo; and 3) reveal NK-specific microRNA patterns and elucidate how they control mRNA targets to regulate NK development and set NK cell activation thresholds. These results will be highly significant, because they will be essential for understanding how NK cells distinguish normal from aberrant cells. Such an understanding will suggest new ways to manipulate NK cells in the therapy of cancer and infectious diseases. PUBLIC HEALTH RELEVANCE: Natural killer (NK) cells kill infected and malignant cells and direct subsequent adaptive immunity. The long-range goal is to use NK cells as effective treatments of cancer and infectious diseases. As the next logical step toward that goal, the current objectives are to further characterize NK gene expression control in normal physiology and in cancers and pre-cancers, such as lymphoma and myelodysplastic syndrome.

描述（由申请人提供）：自然杀伤（NK）细胞杀死感染和恶性细胞，并指导随后的适应性免疫。NK细胞主要通过杀伤细胞免疫球蛋白样受体（KIR）区分正常细胞和异常细胞。尽管KIR基因之间具有高度同源性，但单个NK细胞表达不同数量和组合的克隆限制性KIR（crKIR）基因。与crKIR相反，KIR 2DL 4由所有NK细胞表达，在NK发育期间先于crKIR表达。长期目标是使用NK细胞作为癌症和传染病的有效治疗方法。作为实现这一目标的下一个合乎逻辑的步骤，目前的目标是进一步表征正常生理学和淋巴瘤和骨髓增生异常综合征的表观遗传治疗期间的KIR表达控制。这项研究的基本原理是，一旦更好地理解KIR基因调控，就可以操纵KIR表达，使NK细胞试剂有效地用于癌症和感染性疾病的免疫治疗。在这个提议中，2DL 4和crKIR启动子将被调查，特别注意克服DNA甲基化和抑制染色质的机制。由于对淋巴细胞特异性基因表达如何受癌症和表观遗传治疗的影响知之甚少，我们将研究DNA甲基化和组蛋白去乙酰化酶抑制剂药物如何影响骨髓增生异常综合征和淋巴瘤患者的KIR启动子甲基化、KIR表达和NK细胞活化。这项工作可以解释为什么NK功能在癌症患者中很差，并可能为这些患者提供增强免疫力的策略。我们将对NK细胞microRNA表达及其靶mRNA进行分类，并研究调节“危险”细胞毒性NK细胞和“未经许可”抑制性受体阴性NK细胞的microRNA机制。这将为今后的研究提供必要的基本信息，控制NK发展的健康和疾病的决定。这项研究将1）对控制KIR表达的启动和维持的多层次调控有一个清晰的认识; 2）首次建立表观遗传疗法如何影响体内非恶性人类淋巴细胞基因表达和功能; 3）揭示NK特异性microRNA模式，并阐明它们如何控制mRNA靶点来调节NK发育和设定NK细胞活化阈值。这些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。这种理解将为在癌症和传染病的治疗中操纵NK细胞提供新的方法。公共卫生相关性：自然杀伤（NK）细胞杀死感染和恶性细胞，并指导随后的适应性免疫。长期目标是使用NK细胞作为癌症和传染病的有效治疗方法。作为实现这一目标的下一个合乎逻辑的步骤，目前的目标是进一步表征正常生理学和癌症及癌前病变（如淋巴瘤和骨髓增生异常综合征）中的NK基因表达控制。