Regulation of NFAT by the Rho GEF, GEF-H1

描述(申请人提供)：T细胞是防御感染所必需的。它们的作用是检测发出感染信号的抗原，并做出适当的反应。激活始于从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，调节对特定入侵的反应。NFAT是一种转录因子，在TCR刺激下对细胞的存活、增殖和效应器功能是必需的。在老年人群中，它的激活明显减少，这导致疫苗预防感染的有效性降低，并增加了感染的风险 那些没有预防性疫苗的感染。对NFAT途径的未知激活物进行了筛选，并确定了全球环境基金-H1。进一步的实验表明，向NFAT发送TCR信号需要使用全球环境基金-H1。概述的研究的目标是展示环境基金-H1如何在该途径中发挥作用。制定了由三个目标组成的战略。最初，TCR-to-NFAT途径中的步骤将在缺乏全环基金-H1的细胞中进行分析，以确定该途径中全环基金-H1的作用水平。下一步，将测试环境基金-H1中每个结构域的必要性，以恢复环境基金-H1缺陷细胞中的NFAT激活。最后，将在通向NFAT的TCR途径中测试全环基金-H1目标RhoA的作用。这项研究将扩大我们对T细胞调节的理解，并确定潜在的靶点，用于开发治疗方法，以增强老年患者的次优免疫反应。 与公共健康相关：随着我们年龄的增长，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工作的了解，以便我们可以制定有针对性的策略，以增强老年患者的次优反应。

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.