Understanding the early evolution of steatocystoma cyst formation

了解脂肪囊瘤囊肿形成的早期演变

• 批准号: MR/Z50399X/1
• 负责人: Marianne De Brito
• 金额: $ 59.68万
• 依托单位: Queen Mary University of London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FZ50399X%2F1
• 关键词: Understanding; early; evolution; steatocystoma; cyst

Steatocystoma multiplex (SM) is a debilitating disease characterised by the development of multiple cysts in the skin of the proximal limbs and trunk. This can cause significant psychosocial distress, particularly given the time of onset, classically at adolescence. Furthermore, these cysts frequently get inflamed, becoming red and painful and affecting mobility and sexual function, causing embarrassment. There is no cure. Current treatments, including serial excision or drainage, are time consuming and not preventative.In SM, a change to the keratin-17 gene (KRT17) which encodes the K17 protein involved in the formation of sebaceous glands (structures near hairs which have special oil-secreting cells) stops it functioning normally, although we do not understand why this causes cysts to form. The cyst wall structure and protein expression pattern of the cysts which form resembles the sebaceous duct from which sebum (oil on surface of the skin) is excreted from the sebaceous gland. The cysts are located in the dermis (the middle layer of the skin) but pathology studies from decades ago identified a fibrous band connection from the cyst to the epidermis (the top layer of skin). We do not know why or how this forms.Our aim is to understand what genes and signalling pathways cause these cysts to form to enable us to target them with therapies to prevent cyst formation.We have preliminary data that the epidermis (upper layer of the skin) overlying small, early cysts is highly abnormal (with lots of small dividing skin cells) and may contain sebocytes (specialist cells of the sebaceous gland described above). We will investigate this by analysing what genes are expressed by the skin overlying and surrounding the cyst in early cysts (via spatial transcriptomics). We will then validate possible signalling pathways identified by these genes by staining sections of these cysts for the proteins the genes express. We will also investigate the lipid composition of the cyst contents and sebum on the skin of patients compared to unaffected control participants in collaboration with our lipid expert partners in Italy. Modern lipid analysis has never before been attempted in SM. We think the sebum of SM patients may be pro-inflammatory and this could be what causes individual steatocystomas to become inflamed. Understanding this will give us insights into how to treat and stop the inflammation happening. We will then use cells carrying the altered KRT17 gene and normal control cells to test treatments targeting the signalling pathways we have found from the identified genes and proteins. Possible effective treatments could then be taken into drug development pathways or a drug repurposing pathway to ultimately offer a treatment to patients suffering from this debilitating disease.Apart from SM, altered KRT17 expression is also found in other conditions, including hidradenitis suppurativa (causing boils in the groin and underarm areas) which is clinically similar to inflamed SM, psoriasis and many cancers, where it is a well recognised poor prognostic indicator. Insights into KRT17-related pathways may also inform understanding of the pathophysiology and treatment of these conditions. Increasing understanding of the KRT17 gene may also help elucidate the function and roles of the many keratin proteins, which are highly expressed throughout the skin and associated structures such as the hair follicle and sweat glands and can cause disease when there is a genetic error (mutation).

Steatocystoma多路复用（SM）是一种使人衰弱的疾病，其特征是在近端四肢和躯干皮肤中发育多个囊肿。这可能会引起严重的社会心理困扰，尤其是考虑到发作时，在青春期是经典的。此外，这些囊肿经常发炎，变红，痛苦，影响流动性和性功能，从而造成尴尬。无法治愈。当前的处理，包括连续切除或排水，是耗时而不是预防性的。囊肿壁的结构和蛋白质表达模式类似于皮脂管，从皮脂腺中排出皮成为皮脂（皮肤上的油）的皮脂管。囊肿位于真皮（皮肤的中间层）中，但几十年前的病理研究确定了从囊肿到表皮的纤维带连接（皮肤的顶层）。 We do not know why or how this forms.Our aim is to understand what genes and signalling pathways cause these cysts to form to enable us to target them with therapies to prevent cyst formation.We have preliminary data that the epidermis (upper layer of the skin) overlying small, early cysts is highly abnormal (with lots of small dividing skin cells) and may contain sebocytes (specialist cells of the sebaceous gland described above).我们将通过分析在早期囊肿中（通过空间转录组学）中的皮肤上覆和囊肿表达的基因来研究这一点。然后，我们将通过对基因表达的蛋白质的这些囊肿染色部分来验证这些基因鉴定的可能的信号传导途径。与未受影响的对照参与者与我们在意大利的脂质专家合作伙伴合作，我们还将研究患者皮肤上囊肿含量和皮脂的脂质组成。现代脂质分析从未在SM中尝试过。我们认为，SM患者的皮脂可能是促炎症性的，这可能是导致单个脂肪囊肿的发炎的原因。理解这将使我们了解如何治疗和阻止发生炎症。然后，我们将使用携带改变的KRT17基因和正常对照细胞的细胞来测试针对我们从确定的基因和蛋白质发现的信号传导途径的处理。 Possible effective treatments could then be taken into drug development pathways or a drug repurposing pathway to ultimately offer a treatment to patients suffering from this debilitating disease.Apart from SM, altered KRT17 expression is also found in other conditions, including hidradenitis suppurativa (causing boils in the groin and underarm areas) which is clinically similar to inflamed SM, psoriasis and many cancers, where it is a well recognised poor prognostic 指标。对KRT17相关途径的见解也可能使人们了解对这些疾病的病理生理学和治疗。对KRT17基因的越来越多也可能有助于阐明许多角蛋白蛋白的功能和作用，这些角蛋白蛋白在整个皮肤以及相关结构（例如毛囊和汗腺）中高度表达，并在遗传误差（突变）时会引起疾病。