Understanding the early evolution of steatocystoma cyst formation

多发性脂肪囊瘤（SM）是一种使人衰弱的疾病，其特征是在近端肢体和躯干的皮肤中形成多个囊肿。这可能会造成严重的心理社会困扰，特别是考虑到发病时间，典型的是在青春期。此外，这些囊肿经常发炎，变红和疼痛，影响流动性和性功能，造成尴尬。无药可救。目前的治疗方法，包括连续切除或引流，都是耗时且无法预防的。在SM中，角蛋白-17基因（KRT 17）的改变会阻止其正常功能，尽管我们不知道为什么会导致囊肿的形成。角蛋白-17基因编码的K17蛋白参与皮脂腺（靠近头发的结构，具有特殊的油脂分泌细胞）的形成。所形成的囊肿的囊壁结构和蛋白质表达模式类似于皮脂腺导管，皮脂（皮肤表面上的油）从所述皮脂腺导管从皮脂腺排出。囊肿位于真皮（皮肤的中间层），但几十年前的病理学研究发现，囊肿与表皮（皮肤的顶层）之间存在纤维带连接。我们不知道为什么或如何形成。我们的目标是了解哪些基因和信号通路导致这些囊肿形成，使我们能够用治疗方法来预防囊肿形成。我们有初步的数据表明，表皮覆盖在小的早期囊肿上的皮肤（上层皮肤）是高度异常的（具有许多小的分裂的皮肤细胞），并且可能含有皮脂腺细胞（上述皮脂腺的专门细胞）。我们将通过分析在早期囊肿中覆盖和包围囊肿的皮肤表达哪些基因（通过空间转录组学）来研究这一点。然后，我们将通过对这些基因表达的蛋白质的包囊切片进行染色来验证这些基因所识别的可能的信号通路。我们还将与我们在意大利的脂质专家合作伙伴合作，研究患者皮肤上囊肿内容物和皮脂的脂质组成，并与未受影响的对照参与者进行比较。在SM中从未尝试过现代脂质分析。我们认为SM患者的皮脂可能是促炎性的，这可能是导致个体脂肪囊瘤发炎的原因。了解这一点将使我们了解如何治疗和阻止炎症的发生。然后，我们将使用携带改变的KRT 17基因的细胞和正常对照细胞来测试针对我们从鉴定的基因和蛋白质中发现的信号通路的治疗。可能的有效治疗方法可以进入药物开发途径或药物再利用途径，最终为患有这种衰弱性疾病的患者提供治疗。除了SM，在其他疾病中也发现了KRT 17表达的改变，包括化脓性汗腺炎（引起腹股沟和腋下区域的疖子），临床上类似于发炎的SM，牛皮癣和许多癌症，它是公认的不良预后指标。对KRT 17相关通路的深入了解也可能有助于了解这些疾病的病理生理学和治疗。增加对KRT 17基因的了解也可能有助于阐明许多角蛋白的功能和作用，这些角蛋白在整个皮肤和相关结构（如毛囊和汗腺）中高度表达，并且当存在遗传错误（突变）时可能导致疾病。

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).