Regulation of NFAT by the Rho GEF, GEF-H1

Rho GEF、GEF-H1 对 NFAT 的监管

• 批准号: 8397249
• 负责人: Corinne Hamblet
• 金额: $ 4.22万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8397249
• 关键词: Affect; Age; Antigens; B-Lymphocytes; Binding; Biological Assay; Bystander Effect; Calcineurin; Cell Line; Cell Survival; Cell division; Cells; Cytoskeleton; DAG/PE-Binding Domain; DH Domain; Defect; Dominant-Negative Mutation; Due Process; Elderly; Fluorescence Microscopy; Generic Drugs; Genes; Goals; Guanine Nucleotide Exchange Factors; Guanine Nucleotides; Guanosine Triphosphate; Guanosine Triphosphate Phosphohydrolases; Human; Immigration; Immune response; Immune system; Infection; Knowledge; Link; Lymphocyte; Lymphocyte Activation; Lymphoid; Microtubules; Modeling; NFAT Pathway; Normal Cell; Nuclear; Organ; Pathway interactions; Phenotype; Phosphorylation; Point Mutation; Population; Production; RNA Interference; Receptor Signaling; Receptors, Antigen, B-Cell; Regulation; Research; Rest; Risk; Role; STIM1 gene; Signal Transduction; Site; Specificity; T Cell Receptor Signaling Pathway; T cell regulation; T-Cell Development; T-Cell Receptor; T-Lymphocyte; Testing; Thymus Gland; Tissues; Transcript; Vaccination; Vaccines; Work; expression cloning; knock-down; mutant; older patient; release of sequestered calcium ion into cytoplasm; research study; response; restoration; rho; small hairpin RNA; therapeutic development; transcription factor

DESCRIPTION (provided by applicant): T cells are necessary for defense against infections. Their role is to detect antigens that signal infection and mount an appropriate response. Activation begins with the signaling pathways from the T cell receptor (TCR) to a suite of transcription factors that induce the production of new genes, tuning the response to the specific invasion. NFAT is a transcription factor necessary for cell survival, proliferation, and effector function upon TCR stimulation. Its activation is markedly reduced in elderly populations, which leads to reduced efficacy of vaccinations in protecting against infection, and an increased risk of those infections without a preventative vaccine. A screen was performed for unknown activators of the NFAT pathway, and identified GEF-H1. Additional experiments revealed that GEF-H1is required for TCR signaling to NFAT. The goal of the outlined research is to show how GEF-H1 functions in the pathway. A strategy composed of three aims has been devised. Initially, steps in the TCR-to-NFAT pathway will be assayed in cells lacking GEF-H1 to determine what level in the pathway GEF-H1 acts. Next, the necessity of each domain in GEF-H1 will be tested for the restoration of NFAT activation in the GEF-H1 deficient cells. Finally, the role of the GEF-H1 target, RhoA, will be tested in the TCR pathway to NFAT. This research will expand our understanding of the regulation of T cells, and identify potential targets for the development of therapeutics to enhance sub-optimal immune responses seen in elderly patients. PUBLIC HEALTH RELEVANCE: As we age our immune system becomes less effective. This research would expand our knowledge of how a healthy immune response works, so that we may develop targeted strategies for enhancing the sub-optimal responses seen in elderly patients.

描述（由申请人提供）：T细胞是防御感染所必需的。它们的作用是检测信号感染的抗原并产生适当的反应。激活开始于从T细胞受体（TCR）到一系列转录因子的信号通路，这些转录因子诱导新基因的产生，从而调节对特定入侵的反应。NFAT是TCR刺激后细胞存活、增殖和效应子功能所必需的转录因子。它的激活在老年人群中明显减少，这导致疫苗接种在预防感染方面的效力降低，并且增加了感染的风险。 这些感染没有预防性疫苗。对NFAT途径的未知激活剂进行筛选，并鉴定出GEF-H1。进一步的实验表明，GEF-H1是TCR信号传导至NFAT所必需的。概述研究的目标是显示GEF-H1如何在通路中发挥作用。制定了一项由三个目标组成的战略。最初，将在缺乏GEF-H1的细胞中测定TCR至NFAT途径中的步骤，以确定GEF-H1在途径中的作用水平。接下来，将测试GEF-H1中每个结构域对于GEF-H1缺陷细胞中NFAT活化的恢复的必要性。最后，GEF-H1靶标RhoA的作用将在TCR途径中测试到NFAT。这项研究将扩大我们对T细胞调节的理解，并确定开发治疗方法的潜在靶点，以增强老年患者中观察到的次优免疫反应。 公共卫生相关性：随着年龄的增长，我们的免疫系统变得不那么有效。这项研究将扩大我们对健康免疫反应如何起作用的了解，以便我们可以制定有针对性的策略来增强老年患者中出现的次优反应。