Role of TRPV channels in the pathogenesis of Systemic Sclerosis vasculopathy

TRPV 通道在系统性硬化症血管病发病机制中的作用

• 批准号: 8826028
• 负责人: SERGIO A JIMENEZ
• 金额: $ 17.05万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8826028
• 关键词: Affect; Agonist; Animal Model; Autoimmune Diseases; Blood Vessels; Cations; Cells; Data; Dermal; Development; Disease; Effector Cell; Endothelial Cells; Etiology; Event; Fibroblasts; Fibrosis; Functional disorder; Generations; Genes; Growth Factor; Health; Human; Immune; Individual; Infiltration; Inflammation; Inflammatory; Ion Channel; Knock-out; Lesion; Lung; Mediating; Mesenchymal; Molecular; Molecular Target; Mus; Myofibroblast; Organ; Pathogenesis; Pathologic; Patients; Phenotype; Play; Process; Publishing; Role; Scleroderma; Sensory; Signal Transduction; Skin; Stimulus; Stress; Systemic Scleroderma; TRPV1 gene; Temperature; Testing; Tissue Model; Tissues; Transforming Growth Factor beta; Transforming Growth Factors; Vanilloid; Vascular Diseases; autocrine; base; capsaicin receptor; connective tissue growth factor; cytokine; improved; in vivo; macrophage; member; mortality; new therapeutic target; novel; novel therapeutic intervention; overexpression; polypeptide; receptor; receptor function; sensory stimulus

DESCRIPTION (provided by applicant): Transient receptor potential (TRP) channels are a superfamily of polymodal receptor cation channels that mediate environmental and sensory signal transduction. TRP cation channel, subfamily V (TRPV) members are sensitive to various environmental stimuli such as: temperature changes, osmosensitivity and stress, and their ubiquitous expression suggests a role in both sensory and nonsensory transduction. Recently, we made the highly provocative observation that TRPV2 was profoundly underexpressed (greater than 20-fold) in Systemic Sclerosis (SSc) dermal fibroblasts compared to those from normal individuals, suggesting that TRPV channels may play a role in the pathogenesis of SSc. Other published studies have shown that TRPV1 and TRPV4 participate in the development of fibrotic lesions in animal models of fibrosis. Based on these studies we propose the hypothesis that: TGF-ß and TRPV channels establish an autocrine loop in fibroblasts and endothelial cells (EC) where TGF-ß expression decreases the expression of TRPV1 and TRPV2 and induces the expression of TRPV4. The reduction of TRPV1 and TRPV2 and the increase in TRPV4 in turn induce and maintain elevated TGF-ß levels creating a repetitive cycle which triggers myofibroblast differentiation in quiescent fibroblasts and induces endothelial to mesenchymal transition (EndoMT) in EC resulting in progressive tissue fibrosis and fibroproliferative vasculopathy. To test this hypothesis we will pursue the following Specific Aims: SPECIFIC AIM 1: Examine the effects of TRPV1, TRPV2 and TRPV4 agonists and antagonists in the presence and absence of TGF-ß, on the expression of profibrotic genes and of genes associated with myofibroblast activation in human dermal fibroblasts and with EndoMT in human dermal and pulmonary microvascular EC. SPECIFIC AIM 2: Evaluate the in vivo effects of Trpv1, Trpv2 and Trpv4 knockout employing the TGF-ss overexpression murine model of tissue fibrosis. Since there is currently no effective disease-modifying therapy to improve the devastating health consequences and high mortality associated with SSc, an urgent unmet need exists to identify potential targets to develop such therapies. The strengths of this proposal are: 1. It is supported by strong Preliminary Data demonstrating that alterations of the activity of TRPV1 and TRPV2 participate in the phenotypic differentiation of fibroblasts into activated myofibroblasts and in te induction of EndoMT in murine EC; and 2. They will provide valuable information regarding the initial molecular events that couple sensory signal transduction, inflammation and fibrosis in SSc. Thus, we believe these studies may provide important clues regarding SSc pathogenesis, and may identify potential novel therapeutic targets for this currently incurable disease.

描述（由申请人提供）：瞬时受体电位（TRP）通道是介导环境和感觉信号转导的多模式受体阳离子通道的超家族。 TRP 阳离子通道 V 亚家族 (TRPV) 成员对各种环境刺激敏感，例如：温度变化、渗透敏感性和应激，其普遍表达表明在感觉和非感觉转导中发挥作用。最近，我们进行了一项极具争议性的观察，即与正常个体相比，TRPV2 在系统性硬化症 (SSc) 真皮成纤维细胞中表达严重不足（超过 20 倍），这表明 TRPV 通道可能在 SSc 的发病机制中发挥作用。其他已发表的研究表明，TRPV1 和 TRPV4 参与纤维化动物模型中纤维化病变的发展。基于这些研究，我们提出以下假设：TGF-β 和 TRPV 通道在成纤维细胞和内皮细胞 (EC) 中建立自分泌环，其中 TGF-β 表达降低 TRPV1 和 TRPV2 的表达并诱导 TRPV4 的表达。 TRPV1 和 TRPV2 的减少以及 TRPV4 的增加反过来诱导并维持升高的 TGF-β 水平，形成一个重复循环，触发静止成纤维细胞中的肌成纤维细胞分化，并诱导 EC 中的内皮向间质转化 (EndoMT)，从而导致进行性组织纤维化和纤维增殖性血管病。为了检验这一假设，我们将追求以下具体目标： 具体目标 1：检查 TRPV1、TRPV2 和 TRPV4 激动剂和拮抗剂在存在和不存在 TGF-β 的情况下对人真皮成纤维细胞中促纤维化基因和与肌成纤维细胞活化相关的基因表达的影响，以及对人真皮和肺微血管 EC 中 EndoMT 的影响。具体目标 2：使用 TGF-β 过度表达小鼠组织纤维化模型评估 Trpv1、Trpv2 和 Trpv4 敲除的体内效果。由于目前尚无有效的疾病缓解疗法来改善与 SSc 相关的破坏性健康后果和高死亡率，因此迫切需要确定开发此类疗法的潜在目标，但未得到满足。该提案的优点是： 1. 支持 强有力的初步数据表明，TRPV1 和 TRPV2 活性的改变参与成纤维细胞向活化肌成纤维细胞的表型分化，并参与小鼠 EC 中 EndoMT 的诱导； 2. 他们将提供有关 SSc 中感觉信号转导、炎症和纤维化耦合的初始分子事件的有价值的信息。因此，我们相信这些研究可能提供有关 SSc 发病机制的重要线索，并可能为这种目前无法治愈的疾病确定潜在的新治疗靶点。