NFAT Transcription in Vascular Smooth Muscle

血管平滑肌中的 NFAT 转录

• 批准号: 6745945
• 负责人: Thomas J. Murphy
• 金额: $ 38万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6745945
• 关键词: blood vessel disorder; calcineurin; cyclosporines; drug adverse effect; gene expression; genetic transcription; interleukin 6; laboratory mouse; nuclear receptors; pharmacokinetics; prostaglandin endoperoxide synthase; protein isoforms; protein kinase A; recombinant proteins; tissue /cell culture; transcription factor; vascular smooth muscle

DESCRIPTION (provided by the applicant): The immunosuppressants cyclosporin A (CsA) and FK506 cause a spectrum of serious side effects, including impaired cardiovascular function. This is not only a serious clinical problem, but also indicates that cellular processes affected by immunosuppressant are crucial for the maintenance of normal cardiovascular homeostasis. Through binding to either of two distinct cellular adapters, both drugs inhibit the phosphatase calcineurin. A family of transcription factors termed the nuclear factors of activated T-cells (NFAT) are well-known calcineurin substrates. Although initially considered T-cell restricted, studies indicate that NFAT isoforms are widely distributed in non-lymphoid tissues throughout the body. The applicant has published several studies supporting the general notion that NFAT can serve as a transcriptional effector for signaling evoked by various hormones, autacoids and growth factors within subsets of vascular smooth muscle and endothelial cells. We speculate that NFAT participates in the modulation of vascular gene expression programs elicited by such physiological agonists and that interference with NFAT mediated transcription may contribute to immunosuppressant drug toxicity. If so, on balance, NFAT likely serves as a key regulator of important homeostatic processes, and its targets would be of great interest to discover. General objectives of this project include deriving a better understanding of how NFAT mediated transcription operates in a vasculature smooth muscle cell context, and what genes it may be involved in regulating. To explore this, we will assess whether four distinct NFAT isoforms are differentially regulated and drive unique patterns of vascular gene expression. Since no NFAT gene targets in smooth muscle cells have been definitively described, we will carry forward studies that strongly support the hypothesis that NFATs trans-activate the COX-2 and IL-6 genes within VSMC. We will also study how co-activation of cAMP-dependent kinase pathways modulate NFAT transcription. Lastly, we will examine the physiologic consequences of disrupted NFAT function by studying how CsA treatment and NFAT gene ablation influence vascular function using murine models. The project will exploit innovative and powerful recombinant gene expression techniques in cultured cell models, coupled with state-of-the-art physiological assessments. Our expected findings are likely to provide important new insights into the role of NFAT in vascular smooth muscle and its relationship to immunosuppressant-induced vascular dysfunction.

性状（由申请人提供）：免疫抑制剂环孢菌素A (CsA)和FK 506引起一系列严重的副作用，包括 心血管功能这不仅是一个严重的临床问题， 表明受免疫抑制剂影响的细胞过程对于 维持正常的心血管内稳态。通过绑定到 两种不同的细胞适配器，两种药物都抑制磷酸酶 钙调神经磷酸酶一个转录因子家族，称为核因子， 活化的T细胞（NFAT）是众所周知的钙调磷酸酶底物。虽然 最初被认为是T细胞限制性的，研究表明NFAT亚型是 广泛分布于全身的非淋巴组织中。申请人 发表了几项研究，支持NFAT可以服务于 作为由各种激素引起的信号传导的转录效应物， 血管平滑肌亚群内的自体激素和生长因子， 内皮细胞我们推测，NFAT参与了调节 由这种生理激动剂引发的血管基因表达程序， 干扰NFAT介导的转录可能有助于 免疫抑制剂药物毒性。如果是这样，总的来说，NFAT可能是一个关键 调节重要的稳态过程，其目标将是伟大的 兴趣去发现。该项目的总体目标包括： 更好地了解NFAT介导的转录如何在一个 血管平滑肌细胞背景，以及可能涉及哪些基因 调节。为了探索这一点，我们将评估四种不同的NFAT亚型是否 受到不同的调节，并驱动血管基因的独特模式， 表情由于在平滑肌细胞中没有NFAT基因靶点， 明确描述，我们将继续进行研究，大力支持 假设NFAT反式激活VSMC内的考克斯-2和IL-6基因。我们 还将研究cAMP依赖性激酶通路的共激活如何调节 NFAT转录。最后，我们将研究的生理后果， 通过研究CsA治疗和NFAT基因切除如何破坏NFAT功能， 影响血管功能。该项目将利用 培养细胞中创新和强大的重组基因表达技术 模型，再加上最先进的生理评估。我们预期的 这些发现可能会为NFAT在以下方面的作用提供重要的新见解： 血管平滑肌及其与免疫抑制剂诱导的 血管功能障碍