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Functional and molecular diversity of skin fibroblasts in systemic sclerosis.

系统性硬化症中皮肤成纤维细胞的功能和分子多样性。

基本信息

批准号：
MR/T001631/1
负责人：
Kristina Elizabeth Neergaard Clark
金额：
$ 33.28万
依托单位：
University College London
依托单位国家：
英国
项目类别：
Fellowship
财政年份：
2019
资助国家：
英国
起止时间：
2019 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FT001631%2F1
关键词：
Functional molecular diversity skin fibroblasts

项目摘要

Systemic sclerosis (SSc), also called scleroderma, is an uncommon autoimmune rheumatic condition leading to thickened skin (sclerosis) with fibrosis, or scarring, in the skin and vital organs such as the lungs and heart, kidneys and bowel. These complications are responsible for major impact of the disease on almost all aspects of everyday life and in the most severe cases can lead to death. The pattern and severity of skin thickening can be used to identify cases most at risk of severe internal organ involvement and reduced long-term survival. However, the relationship between skin disease and overall outcome is imprecise because the basic mechanisms of disease in scleroderma remain poorly understood. The extent of skin involvement helps to classify patients, and distinct trajectories of skin involvement are associated with differing prognosis and survival. As a result, scleroderma remains a challenging disease to treat and is responsible for more deaths than any other rheumatic disease.Although scleroderma is rare, the processes that have malfunctioned and that determine severity of the disease are likely to be relevant to many commoner conditions such as lung and liver fibrosis, or excessive scarring after surgery, burns or skin wounding. In this way scleroderma offers a possible route to understand and ultimately prevent or treat these other important disorders.Previous work in scleroderma has suggested that a key type of cell in the skin and internal organs called the fibroblast acts as a driver of fibrosis in skin disease. Fibroblasts can be grown from small pieces of skin (biopsies) taken under local anaesthetic from scleroderma patients. However only some of the fibroblasts grow out of the biopsy and recent research suggests that these may not be the most important cells determining skin fibrosis. This has limited previous studies because there are likely to be many different types of fibroblasts that have different roles in normal healthy skin and in diseases such as scleroderma.New laboratory techniques provide exciting tools to distinguish between the different populations of fibroblasts in skin and we have developed a new method to isolate different populations of fibroblasts from skin biopsies in scleroderma. This is a major step forward because unlike other cell types, such as immune cells or blood cells, fibroblasts examined using traditional methods and laboratory tools are often indistinguishable from each other. The present application will use modern scientific approaches to examine gene and protein expression and to define the distinct types of fibroblasts in the skin, and further understand their potential importance in the scleroderma disease process. We will ask patients with scleroderma attending our routine clinic to donate small samples of skin and will analyse each cell in the biopsy individually to identify the types of cells present. We expect to find small groups of cells within the biopsy expressing similar proteins. The technique we propose to use has already been applied in rheumatoid arthritis, another autoimmune disease affecting the joints, as well as in healthy skin.We fully expect that there will be different fibroblast populations, and that these will have distinct properties at different stages of scleroderma. Definition of the detailed properties and function of these cells will have implications on future treatment targets and determine which of the emerging therapies for scleroderma will work best for an individual patient. This is vital considering the very high clinical burden of scleroderma and current variation in response to available drugs.As well as providing important information about scarring and fibrosis, this work will also have wider implications on other common autoimmune diseases affecting the skin, such as psoriasis, where there may be overlap in the types of cells driving the disease, and similar treatments may be applicable.

系统性硬化症(SSC)，也称为硬皮病，是一种罕见的自身免疫性风湿病，导致皮肤增厚(硬化症)，皮肤和重要器官如肺、心脏、肾脏和肠道出现纤维化或疤痕。这些并发症是该病对日常生活几乎所有方面造成重大影响的原因，在最严重的情况下可能导致死亡。皮肤增厚的类型和严重程度可以用来确定最有可能严重侵犯内脏和降低长期存活率的病例。然而，皮肤病和总体结果之间的关系是不精确的，因为硬皮病的基本发病机制仍然知之甚少。皮肤受累的程度有助于对患者进行分类，不同的皮肤受累轨迹与不同的预后和生存相关。因此，硬皮病仍然是一种具有挑战性的疾病，治疗起来比其他任何风湿病的死亡人数都多。尽管硬皮病很罕见，但决定疾病严重程度的过程可能与许多常见的疾病有关，如肺和肝纤维化，或手术后的过度疤痕，烧伤或皮肤损伤。通过这种方式，硬皮病提供了一条可能的途径来了解并最终预防或治疗这些其他重要的疾病。以前对硬皮病的研究表明，皮肤和内脏中的一种关键类型的细胞，称为成纤维细胞，是皮肤病纤维化的驱动因素。成纤维细胞可以从硬皮病患者的小块皮肤(活组织检查)中培养出来。然而，只有部分成纤维细胞从活检中生长出来，最近的研究表明，这些细胞可能不是决定皮肤纤维化的最重要的细胞。这限制了以前的研究，因为可能有许多不同类型的成纤维细胞在正常健康的皮肤和硬皮病等疾病中具有不同的作用。新的实验室技术提供了令人兴奋的工具来区分皮肤中不同群体的成纤维细胞，我们开发了一种从硬皮病皮肤活检组织中分离不同群体成纤维细胞的新方法。这是向前迈出的重要一步，因为与免疫细胞或血细胞等其他细胞类型不同，使用传统方法和实验室工具检查的成纤维细胞往往彼此难以区分。目前的应用将使用现代科学方法来检测基因和蛋白质的表达，并确定皮肤中不同类型的成纤维细胞，并进一步了解它们在硬皮病发病过程中的潜在重要性。我们将要求到我们常规诊所就诊的硬皮病患者捐赠少量皮肤样本，并将对活检中的每个细胞进行单独分析，以确定存在的细胞类型。我们希望在活检组织中发现表达相似蛋白质的小群细胞。我们建议使用的技术已经应用于风湿性关节炎，另一种影响关节的自身免疫性疾病，以及健康皮肤。我们完全预计会有不同的成纤维细胞群，这些成纤维细胞在硬皮病的不同阶段将具有不同的特性。对这些细胞的详细特性和功能的定义将对未来的治疗目标产生影响，并决定哪些新兴的硬皮病疗法对个别患者最有效。考虑到硬皮病非常高的临床负担和目前对可用药物的反应变化，这一点至关重要。除了提供关于瘢痕形成和纤维化的重要信息外，这项工作还将对影响皮肤的其他常见自身免疫性疾病，如牛皮癣，其驱动疾病的细胞类型可能存在重叠，以及类似的治疗可能适用。