Controlling collagen deposition by fibroblasts in cutaneous fibrosis by targeting TANGO1 function

纤维化反应可以在几乎任何组织中发展，并且仍然是死亡和经济负担的主要原因。它们可以作为慢性炎症过程的结果而发生，并且其特征在于细胞外基质（ECM）在相应组织中的过度沉积。到目前为止，纤维化组织中最丰富的ECM成分是胶原蛋白I，它的表达和沉积水平非常高，并显示出异常的大分子组织，导致组织结构紊乱，僵硬，挛缩和组织功能障碍。在这个项目中，我们的目标是通过干扰成纤维细胞中胶原蛋白的分泌来改变胶原蛋白的过度沉积，成纤维细胞是主要的胶原蛋白产生细胞类型。我们以前的工作表明，TANGO 1活性对胶原蛋白分泌至关重要。我们现在想要使用TANGO 1抑制剂来调节过度的胶原沉积。因此，我们的目标是确定缺乏和/或减少TANGO 1功能后的分子和细胞机制，并确定细胞反应。将产生特异性肽抑制剂并将其应用于来自健康个体和硬皮病患者的成纤维细胞作为纤维化疾病的模型，以评估减少胶原蛋白分泌的功效和分子机制。将抑制剂应用于小鼠体内皮肤纤维化模型将补充我们的体外机制研究，并表明这种方法是否可能代表一种有前途的治疗概念。

Fibrotic reactions can develop in almost any tissue and still represent a major cause of death and economic burden. They can occur as a consequence of chronic inflammatory processes and are characterized by excessive deposition of extracellular matrix (ECM) in the respective tissues. By far the most abundant ECM constituent in fibrotic tissues is collagen I, which is expressed and deposited at highly elevated levels and shows an abnormal macromolecular organization that leads to a disturbed tissue architecture, enhanced stiffness, contractures and tissue malfunction.In this project, we aim at modifying the excessive deposition of collagen by interfering with its secretion in fibroblasts, which are the main collagen producing cell type. Our previous work shows that TANGO1 activity is crucial for collagen secretion. We now want to use TANGO1 inhibitors to modulate excessive collagen deposition. Therefore, we aim to identify the molecular and cellular mechanisms following lack of and/or reduction of TANGO1 function and determine the cellular response. Specific peptide inhibitors will be generated and applied to fibroblasts from healthy individuals and patients with scleroderma as a model for fibrotic diseases to assess efficacy and molecular mechanisms of reducing collagen secretion. Application of the inhibitors to a murine model of skin fibrosis in vivo will complement our mechanistic in vitro studies and indicate, whether this approach might represent a promising therapeutic concept.