A systems-genetics approach to dissect inflammation in fibrosis

纤维化是指器官或组织中由于修复或反应性过程而形成的过量结缔组织，因此可视为异常或过度的伤口愈合反应。纤维化的发展是各种潜在疾病的结果，并提出了一个主要的未解决的治疗问题，因为仍然没有治愈纤维化。在几乎所有形式的纤维化中，炎症免疫反应发生在早期阶段，现在有越来越多的证据表明，在没有原发性炎症损伤的情况下，纤维化不会发生。伤口愈合是炎症发展为纤维化的一个范例。在伤口愈合和与炎症纤维化（肾和肺纤维化）相关的各种病理中，先天免疫细胞高度代表，其中最丰富的是巨噬细胞。本项目旨在描述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性纤维化的机制，因为伤口愈合的失调导致纤维化。个体之间的遗传变异可能影响其巨噬细胞的激活，并导致伤口愈合的定量变异。我们通过证明遗传异质性小鼠群体中的遗传变异影响巨噬细胞中关键伤口愈合基因的表达及其对伤口愈合的易感性来研究这一假设。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遗传决定因素的全谱是什么？这与与伤口愈合相关的遗传变异性有何关系？为了回答这个问题，我们将使用一种称为系统遗传学的方法，该方法将巨噬细胞中个体之间的遗传变异与基因表达结合起来，构建生物网络，并确定与伤口愈合相关的网络的遗传控制点。使用系统遗传学方法，我们将通过识别可以在炎症性纤维化特征的疾病中研究的新候选基因来发现伤口愈合的新遗传因素。

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.