Breaking a novel feedback loop to inhibit fibrosis

打破新颖的反馈回路来抑制纤维化

基本信息

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
项目类别：
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

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

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项目摘要

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.

抽象的诸如肺纤维化之类的纤维疾病与美国多达45％的死亡有关。在这些疾病中，内部器官中称为纤维化病变的不适当疤痕组织。没有FDA- 逆转纤维化的批准疗法，关于驱动纤维化的机制尚待了解。在小鼠和人肺中的纤维化病变，唾液酸酶的水平有所增加，酶的水平有所增加从细胞外糖蛋白和其他糖缀合物的远端清除唾液酸。唾液酸酶至少通过增加产生的促纤维细胞因子TGF-β1的水平至少在某种程度上可能具有潜在的纤维化。通过某些免疫系统细胞。相反，TGF-β1引起肺上皮细胞，肺成纤维细胞和一些免疫系统细胞上调唾液酸酶。我们的假设是纤维化部分由失控驱动阳性反馈循环，唾液酸酶电势纤维化和纤维化潜力唾液酸酶。支持这个假设，我们发现两种不同的唾液酸酶抑制剂的注射减少了小鼠的肺纤维化博来霉素模型。洞悉似乎是与免疫联系的基本机制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。由于识别纤维化中/已更新的关键唾液酸酶将识别潜力抑制纤维化的靶标，我们的第一个目的是检验以下假设：唾液酸酶称为neu3是主要的潜在纤维化的唾液酸酶。我们的第二个目的是确定哪些免疫系统细胞对唾液酸酶并阐明接收器，从而使免疫系统细胞感知到更新的唾液酸酶，并且因此，确定潜在目标以阻止反馈回路。我们的第三个目的是确定唾液酸酶是如何引起的 TGF-β1的上调，因此基本上是在唾液酸酶传感途径上向后往后工作 2工作。这项工作将有助于阐明一种调节先天免疫系统的新型机制和纤维化，可能会导致纤维化疾病的新疗法。