Transcriptional control of IL-7 receptor (IL-7R) in T cells

T 细胞中 IL-7 受体 (IL-7R) 的转录控制

• 批准号: 8076902
• 负责人: BATU ERMAN
• 金额: $ 5.31万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-10 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8076902
• 关键词: Affect; Affinity; Antibodies; Antiviral Agents; Area; Award; B-Lymphocytes; Binding; Binding Sites; CD8B1 gene; Cell Survival; Cell surface; Cells; Chronic; Collaborations; Communicable Diseases; Data; Databases; Defect; Developing Countries; Development; Effector Cell; Elements; Epigenetic Process; Exposure to; Generations; Genes; Genetic Transcription; Genomics; Goals; Grant; HIV; Health; Hepatitis C virus; Histones; Homeostasis; Hospitalization; Human; Immune response; Immune system; Immunity; Immunologic Deficiency Syndromes; Infection; Information Systems; Institutes; Interleukin 2 Receptor Gamma; Interleukin 7 Receptor; Interleukin-7; Journals; Lead; Life; Longevity; Lymphocyte; Lymphoid; Malignant Neoplasms; Meleagris gallopavo; Memory; Modification; Molecular; Mus; Nucleic Acid Regulatory Sequences; Organ; Parasitic Diseases; Parents; Pattern; Plant Roots; Plasma Cells; Population; Process; Publishing; Receptor Signaling; Regulation; Reporter; Repression; Research; Role; Signal Transduction; Staging; System; T memory cell; T-Cell Development; T-Lymphocyte; Techniques; Testing; Thymus Gland; Time; Transcriptional Regulation; Transgenic Mice; Transgenic Organisms; United States National Institutes of Health; Universities; Vaccination; Vaccines; Virus Diseases; Work; World Health Organization; arm; base; chromatin immunoprecipitation; cytokine; fighting; fitness; global health; histone modification; immune function; improved; in vivo; infectious disease treatment; insight; interest; mortality; mutant; new technology; novel; parent grant; precursor cell; receptor; receptor expression; response; socioeconomics; statistics; stem; thymocyte; tool; transcription factor; web site; years of life lost

DESCRIPTION (provided by applicant): This FIRCA application represents a collaboration between Dr. Susan Kaech at Yale University in the US and Dr. Batu Erman at Sabanci University in Istanbul, Turkey. The Specific Aims stem from those of a parent NIH R01 grant awarded to Dr. Kaech (AI066232) entitled "Regulation of Memory CD8 T cell development." Effective protection against infectious disease is one of the most critical global health problems facing us today, and will continue to as the world population grows to more than 9 billion. For many developing countries, inadequate control or treatment of infectious disease is the root of most socio- economic problems. The website of the Turkish State Institute of Statistics indicates that in 2004, 4.2% of all hospitalizations and 2.5% of all mortality resulted from infectious or parasitic diseases (www.turkstat.gov.tr). Moreover, most recent statistics from the World Health Organization Statistical Information Systems indicate that the years of life lost to communicable diseases is 44% in Turkey whereas it is 9% for the U.S. (www.who.int/whosis/database). Vaccination offers the greatest hope for reducing the negative impact of infectious disease by generating long-lived immunity, which is based primarily on the formation of memory T and B cells and antibody-secreting plasma cells. Over the past decade, our understanding of how these cells are generated by vaccination and infection has increased at a profound rate, but clearly much remains to be discovered. In particular, this FIRCA proposal focuses on enhancing our basic understanding of naove and memory T cell development and homeostasis via the cytokine interleukin-7 (IL-7). Naove and memory T cell survival relies on their ability to "see" IL-7 via the IL-7 receptor (IL-7R), and defects in IL-7:IL-7R signaling cause severe immunodeficiency. In addition, generation of long-lived protective memory T cells requires IL-7R signaling and in many chronic viral infections (such as HIV, HCV, EBV) the antiviral T cells often express low levels of IL-7R and this may contribute to their reduced fitness, longevity and ability to stave off the infection. However, little is known about the transcriptional regulation of IL-7R expression on T cells. Here, we propose to characterize the epigenetic regulation of IL-7R and to identify key regulatory regions and specific transcription factors (TFs) that control IL-7R expression during the development of T cells in the thymus and of memory T cells during viral infection in mice. Specifically, we will characterize histone modifications and the binding of three critical TFs (GABP1, Gfi-1 and NF:B) at three evolutionarily conserved regions of Il7ra. Moreover, we will test the requirement of these TFs bound to Il7ra to activate and repress transcription in vivo using an IL-7R:GFP reporter tg system. The long-term goal is to identify the transcription factors that bind to these regions to regulate IL-7R expression. Deeper insight into the molecular mechanism of IL-7R expression could lead to therapies in which IL-7R expression on T cells could be manipulated, and possibly, improve immune function during infection or vaccination. PUBLIC HEALTH RELEVANCE: Effective vaccines against infectious disease, and perhaps, even cancer depend on generating potent T and B cell responses that create long-lived memory T and B cells and IL-7 is an essential survival factor for these cells. The broad goal of this proposal is to understand how T cells regulate the expression of the survival signaling IL-7 receptor (IL-7R) on their cell surfaces in order to properly develop and persist for long periods of time, and here, we propose to test the requirement of specific genomic elements and transcription factor binding sites for proper expression and repression of IL-7R in T cells in vivo during important developmental stages (as they transit from thymocytes`naove`activated`memory T cells) using a novel tool, an IL-7R:GFP reporter transgenic mouse. This work will provide basic information on the mechanisms of T cell survival and homeostasis and could lead to improved vaccines and T cell-oriented therapies that enhance human health worldwide against infectious disease and cancer.

美国耶鲁大学的Susan Kaech博士和土耳其伊斯坦布尔Sabanci大学的Batu Erman博士合作完成了FIRCA的申请。具体目标来自NIH R01授予Kaech博士(AI066232)的题为“记忆CD8 T细胞发育的调节”的母公司拨款。有效预防传染病是我们今天面临的最严重的全球健康问题之一，随着世界人口增长到90多亿，这种问题将继续存在。对许多发展中国家来说，对传染病的控制或治疗不足是大多数社会经济问题的根源。土耳其国家统计局的网站显示，2004年，4.2%的住院和2.5%的死亡是由传染病或寄生虫病引起的(www.turkstat.gov.tr)。此外，来自世界卫生组织统计信息系统的最新统计数据表明，土耳其因传染病而损失的寿命年数为44%，而美国为9%。疫苗接种提供了最大的希望，通过产生主要基于记忆T和B细胞以及分泌抗体的浆细胞的长期免疫来减少传染病的负面影响。在过去的十年里，我们对疫苗接种和感染是如何产生这些细胞的了解已经以极大的速度增加，但显然还有很多有待发现。特别是，FIRCA的这项建议侧重于通过细胞因子白细胞介素7(IL-7)加强我们对NAOVE和记忆性T细胞发育和动态平衡的基本理解。NAVE和Memory T细胞的生存依赖于它们通过IL-7受体(IL-7R)“看到”IL-7的能力，而IL-7：IL-7R信号的缺陷会导致严重的免疫缺陷。此外，产生长寿的保护性记忆T细胞需要IL-7R信号，在许多慢性病毒感染(如艾滋病毒、丙型肝炎病毒、EBV)中，抗病毒T细胞通常表达低水平的IL-7R，这可能导致它们的适合性、寿命和抵御感染的能力降低。然而，对T细胞上IL-7R表达的转录调控知之甚少。在这里，我们建议表征IL-7R的表观遗传调控，并确定在小鼠胸腺T细胞和病毒感染期间记忆T细胞的发育过程中控制IL-7R表达的关键调节区和特异性转录因子(TF)。具体地说，我们将表征组蛋白的修饰和三个关键的TF(GABP1、GFI-1和NF：B)在Il7ra的三个进化保守区的结合。此外，我们将使用IL-7R：GFP报告TG系统测试这些与Il7ra结合的转录因子在体内激活和抑制转录的需求。长期目标是确定与这些区域结合的转录因子，以调节IL-7R的表达。深入了解IL-7R表达的分子机制可能会导致可以操纵T细胞上IL-7R表达的治疗方法，并可能在感染或疫苗接种期间改善免疫功能。公共卫生相关性：针对传染病的有效疫苗，甚至癌症，依赖于产生强大的T和B细胞反应，从而产生长期记忆的T和B细胞，而IL-7是这些细胞必不可少的生存因素。这项建议的主要目标是了解T细胞如何调节其细胞表面生存信号IL-7受体(IL-7R)的表达，以便正常发育和长期存在，在这里，我们建议使用一种新的工具-IL-7R：GFP报告转基因小鼠-测试在体内重要发育阶段(当T细胞从胸腺细胞转化为激活的记忆T细胞时)T细胞正确表达和抑制IL-7R所需的特定基因组元件和转录因子结合部位。这项工作将提供有关T细胞存活和动态平衡机制的基本信息，并可能导致改进的疫苗和以T细胞为导向的治疗方法，从而在全球范围内增强人类对传染病和癌症的健康。