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: 7694179
• 负责人: BATU ERMAN
• 金额: $ 5.92万
• 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 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7694179
• 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; Developed Countries; Developing Countries; Development; Economics; 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; 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; Turkey bird; United States National Institutes of Health; Universities; Upper arm; Vaccination; Vaccines; Virus Diseases; Work; World Health Organization; alpha chain interleukin-7 receptor; base; chromatin immunoprecipitation; cytokine; fighting; fitness; histone modification; immune function; improved; in vivo; infectious disease treatment; insight; interest; mortality; mutant; new technology; novel; parent grant; precursor cell; public health relevance; response; 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.

描述（由申请人提供）：此 FIRCA 申请代表美国耶鲁大学的 Susan Kaech 博士和土耳其伊斯坦布尔 Sabanci 大学的 Batu Erman 博士之间的合作。具体目标源于授予 Kaech 博士 (AI066232) 的一项母 NIH R01 拨款，题为“记忆 CD8 T 细胞发育的调节”。有效预防传染病是我们当今面临的最严重的全球健康问题之一，并且随着世界人口增长到超过 90 亿，这一问题也将继续存在。对于许多发展中国家来说，传染病控制或治疗不足是大多数社会经济问题的根源。土耳其国家统计局网站显示，2004年，所有住院治疗的4.2%和所有死亡的2.5%是由传染病或寄生虫病引起的（www.turkstat.gov.tr）。此外，世界卫生组织统计信息系统的最新统计数据表明，土耳其因传染病损失的生命年数为 44%，而美国为 9%（www.who.int/whosis/database）。疫苗接种为通过产生长期免疫力来减少传染病的负面影响提供了最大的希望，这种免疫力主要基于记忆 T 和 B 细胞以及抗体分泌浆细胞的形成。在过去的十年中，我们对这些细胞如何通过疫苗接种和感染产生的了解急剧增加，但显然还有很多东西有待发现。特别是，这项 FIRCA 提案侧重于通过细胞因子白细胞介素 7 (IL-7) 增强我们对幼稚 T 细胞和记忆 T 细胞发育和稳态的基本了解。 Naove 和记忆 T 细胞的存活依赖于它们通过 IL-7 受体 (IL-7R)“看到”IL-7 的能力，而 IL-7:IL-7R 信号传导缺陷会导致严重的免疫缺陷。此外，长寿命保护性记忆T细胞的生成需要IL-7R信号传导，并且在许多慢性病毒感染（例如HIV、HCV、EBV）中，抗病毒T细胞通常表达低水平的IL-7R，这可能导致它们的健康度、寿命和避免感染的能力降低。然而，人们对 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 细胞发育过程中和在小鼠病毒感染过程中记忆 T 细胞发育过程中控制 IL-7R 表达的关键调控区域和特定转录因子 (TF)。具体来说，我们将表征 Il7ra 三个进化保守区域的组蛋白修饰和三个关键 TF（GABP1、Gfi-1 和 NF:B）的结合。此外，我们将使用 IL-7R:GFP 报告基因 tg 系统测试这些与 Il7ra 结合的 TF 激活和抑制体内转录的要求。长期目标是鉴定与这些区域结合以调节 IL-7R 表达的转录因子。更深入地了解 IL-7R 表达的分子机制可能会导致可以操纵 T 细胞上的 IL-7R 表达的疗法，并可能改善感染或疫苗接种期间的免疫功能。公共卫生相关性：针对传染病甚至癌症的有效疫苗依赖于产生有效的 T 和 B 细胞反应，从而产生长寿命的记忆 T 和 B 细胞，而 IL-7 是这些细胞的重要生存因子。该提案的总体目标是了解 T 细胞如何调节其细胞表面上生存信号 IL-7 受体 (IL-7R) 的表达，以便正确发育并长期持续存在，在这里，我们建议测试特定基因组元件和转录因子结合位点的要求，以便在重要的发育阶段（当它们从 胸腺细胞“naove”激活的“记忆T细胞）使用一种新工具，即IL-7R：GFP报告基因转基因小鼠。这项工作将提供有关 T 细胞存活和稳态机制的基本信息，并可能导致改进疫苗和 T 细胞导向疗法，从而增强全世界人类健康，对抗传染病和癌症。