A systems-genetics approach to dissect inflammation in fibrosis

纤维化是器官或组织在修复或反应过程中形成过量结缔组织，因此可被视为一种异常或过度的伤口愈合反应。纤维化是各种潜在疾病发展的结果，是一个尚未解决的主要治疗问题，因为目前还没有治愈纤维化的方法。在几乎所有形式的纤维化中，炎症-免疫反应都发生在早期阶段，现在有越来越多的证据表明，在没有原发炎症损害的情况下，不会发生纤维化。伤口愈合代表了炎症向纤维化发展的范例。在伤口愈合和与炎性纤维化(肾脏和肺纤维化)相关的各种病理过程中，天然免疫细胞高度表达，其中最丰富的是巨噬细胞。本项目旨在表征巨噬细胞介导的伤口愈合的分子机制。这将有助于理解炎症纤维化的机制，因为伤口愈合过程中的失调会导致纤维化。个体之间的遗传差异可能会影响他们的巨噬细胞的激活，并导致伤口愈合的数量差异。我们对这一假说进行了研究，发现遗传异质性的小鼠群体中的遗传变异影响了巨噬细胞中关键伤口愈合基因的表达，以及它们对伤口愈合的敏感性。在我们的提案中，我们将提出两个基本问题：小鼠巨噬细胞激活的全谱基因决定因素是什么，这与创伤愈合相关的遗传变异性有何关系？为了回答这个问题，我们将使用一种名为系统遗传学的方法，该方法将个体之间的遗传变异与巨噬细胞中的基因表达相结合，以建立生物网络，并确定与伤口愈合相关的网络的遗传控制点。利用系统遗传学的方法，我们将通过确定可以在以炎性纤维化为特征的疾病中进行研究的新的候选因素，来发现伤口愈合的新的遗传因素。

Fibrosis is the formation of excess connective tissue in an organ or tissue as a result of a reparative or reactive process and could therefore be regarded as an aberrant or excessive wound healing response. Fibrosis develops as a consequence of various underlying diseases and presents a major unsolved therapeutic problem as there is still no cure for fibrosis. In almost all forms of fibrosis, inflammatory-immunological reactions take place in earliest stages and there is now mounting evidence that fibrosis does not occur in the absence of a primary inflammatory insult. Wound healing represents a paradigm for progression of inflammation to fibrosis. In wound healing and various pathologies associated with inflammatory fibrosis (kidney and pulmonary fibrosis), innate immune cells are highly represented, and among the most abundant of these are macrophages.This project aims to characterise the molecular mechanisms involved in macrophage-mediated wound healing. This will allow understanding the mechanisms underlying inflammatory fibrosis as dysregulation in wound healing results in fibrosis.Genetic variation among individuals could affect the activation of their macrophages and cause quantitative variability in wound healing. We investigated this hypothesis by showing that genetic variation in a genetically heterogeneous mice population affects the expression of key wound healing genes in their macrophages and their susceptibility to wound healing. In our proposal, we will ask two fundamental questions: What is the full spectrum of the genetic determinants of macrophage activation in mice and how does this relate to genetic variability associated with wound healing? To answer this, we will use an approach called systems-genetics which integrates genetic variation between individuals with gene expression in macrophages to build biological networks and identify the genetic control points of networks associated with wound healing. Using the systems-genetics approach, we will find novel genetic factors for wound healing by identifying novel candidates that could be studied in diseases characterised by inflammatory fibrosis.