Breaking a novel feedback loop to inhibit fibrosis

打破新颖的反馈回路来抑制纤维化

• 批准号: 9472092
• 负责人: Richard H Gomer
• 金额: $ 35.8万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9472092
• 关键词: Affect; Amyloid; Attenuated; Automobile Driving; Bleomycin; Bronchoalveolar Lavage Fluid; CD209 gene; Cells; Cessation of life; Cicatrix; Disease; Disease Progression; Distal; Enzymes; Epithelial Cells; FDA approved; Feedback; Fibroblasts; Fibrosis; Glycoconjugates; Glycoproteins; Goals; Human; Immune system; Injections; Innate Immune System; Lead; Lectin Receptors; Lesion; Ligands; Link; Lung; Mammals; Mediating; Modeling; Mus; Neuraminidase; Oligosaccharides; Organ; Oseltamivir; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Phenotype; Play; Population; Pulmonary Fibrosis; Role; Runaway; Sentinel; Serum; Sialic Acids; Testing; Therapeutic; Tissues; Transforming Growth Factors; Up-Regulation; Work; cytokine; extracellular; idiopathic pulmonary fibrosis; inhibitor/antagonist; insight; macrophage; monocyte; mouse model; novel; novel strategies; novel therapeutics; receptor; response; sugar

Abstract Fibrosing diseases such as pulmonary fibrosis are associated with up to 45% of the deaths in the US. In these diseases, inappropriate scar tissue called fibrotic lesions forms in internal organs. There are no FDA- approved therapies that reverse fibrosis, and much remains to be known about mechanisms driving fibrosis. In fibrotic lesions in mouse and human lungs, there is an increase in the levels of sialidases, enzymes that remove sialic acids from the distal tips of extracellular glycoproteins and other glycoconjugates. Sialidases appear to potentiate fibrosis at least in part by increasing levels of the pro-fibrotic cytokine TGF-β1 produced by some immune system cells. Conversely, TGF-β1 causes lung epithelial cells, lung fibroblasts, and some immune system cells to upregulate sialidases. Our hypothesis is that fibrosis is driven in part by a runaway positive feedback loop where sialidase potentiates fibrosis and fibrosis potentiates sialidase. In support of this hypothesis, we found that injections of two different sialidase inhibitors reduce pulmonary fibrosis in the mouse bleomycin model. To gain insight into what appears to be a fundamental mechanism linking the immune system to lung epithelial cells and fibroblasts, as well as a mechanism that helps drive fibrosis, we propose three specific aims. Since identifying the key sialidase(s) that is/are upregulated in fibrosis will identify potential targets to inhibit fibrosis, our first aim is to test the hypothesis that a sialidase called NEU3 is the major sialidase that potentiates fibrosis. Our second aim is to determine which immune system cells respond to sialidases and elucidate the receptor(s) whereby immune system cells sense the upregulated sialidases, and thus identify potential targets to block the feedback loop. Our third aim is to determine how sialidases cause an upregulation of TGF-β1, thus essentially working backwards on the sialidase sensing pathway toward the Aim 2 work. Together, this work will help to elucidate a novel mechanism that regulates the innate immune system and fibrosis, and may lead to new therapies for fibrosing diseases.

抽象的 在美国，高达 45% 的死亡与肺纤维化等纤维化疾病有关。 在这些疾病中，内脏器官中会形成称为纤维化病变的不适当的疤痕组织。没有FDA- 逆转纤维化的疗法已获得批准，但关于纤维化的驱动机制仍有许多待了解。在 小鼠和人类肺部的纤维化病变中，唾液酸酶的水平增加，这种酶 去除细胞外糖蛋白和其他糖复合物远端的唾液酸。唾液酸酶 似乎至少部分通过增加产生的促纤维化细胞因子 TGF-β1 的水平来增强纤维化 由一些免疫系统细胞。相反，TGF-β1 会导致肺上皮细胞、肺成纤维细胞和一些细胞 免疫系统细胞上调唾液酸酶。我们的假设是纤维化部分是由失控引起的 正反馈回路，唾液酸酶增强纤维化，纤维化增强唾液酸酶。为了支持这一点 假设，我们发现注射两种不同的唾液酸酶抑制剂可以减少小鼠的肺纤维化 博莱霉素模型。深入了解连接免疫的基本机制 我们提出，肺上皮细胞和成纤维细胞的系统，以及有助于驱动纤维化的机制 三个具体目标。由于确定在纤维化中上调的关键唾液酸酶将确定潜在的 为了抑制纤维化，我们的第一个目标是检验以下假设：一种称为 NEU3 的唾液酸酶是主要的 增强纤维化的唾液酸酶。我们的第二个目标是确定哪些免疫系统细胞会对 唾液酸酶并阐明免疫系统细胞感知上调唾液酸酶的受体，以及 从而确定阻止反馈循环的潜在目标。我们的第三个目标是确定唾液酸酶如何引起 TGF-β1 的上调，因此本质上是在唾液酸酶传感途径上向后工作以实现目标 2 工作。总之，这项工作将有助于阐明调节先天免疫系统的新机制 和纤维化，并可能导致纤维化疾病的新疗法。