Ceramide Analog Control of Cutaneous Inflammation

神经酰胺类似物控制皮肤炎症

• 批准号: 10368633
• 负责人: JACK L ARBISER
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2022-04-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10368633
• 关键词: Actinic keratosis; Address; Adjuvant; Adrenal Cortex Hormones; Adult; Affect; Alkaloids; Amino Acids; Anti-Infective Agents; Anti-Inflammatory Agents; Antiinflammatory Effect; Ants; Atopic Dermatitis; Biochemical; Biological Products; C-terminal; Cells; Ceramides; Chimeric Proteins; Communicable Diseases; Cutaneous; Data; Dendritic Cells; Disease; Down-Regulation; Elderly; Emollients; Female; Firefly Luciferases; Health; Immune; Immunosuppressive Agents; Impairment; Individual; Infection; Infectious Skin Diseases; Inflammation; Inflammatory; Interleukin-1 beta; Interleukin-12; Interleukin-13; Interleukin-17; Interleukin-4; Knockout Mice; Link; Luciferases; Manuscripts; Modeling; Mus; Mutation; N-terminal; Pathway interactions; Penetration; Play; Population; Pre-Clinical Model; Preparation; Procedures; Property; Protocols documentation; Psoriasis; Reporter; Resolution; Retinoids; Role; Running; Signal Pathway; Skin; Sphingosine; Sphingosine-1-Phosphate Receptor; Staphylococcus aureus; Stasis dermatitis; Steroids; T-Lymphocyte; TNF gene; Testing; Up-Regulation; Varicose Ulcer; Venoms; Veterans; Vitamin D; Water; alternative treatment; analog; base; conventional therapy; cytokine; efficacy evaluation; filaggrin; innovation; interleukin-22; interleukin-23; male; novel; repaired; response; restoration; side effect; single cell analysis; single molecule; skin disorder; sphingosine 1-phosphate; vaccine development

Common skin disorders with impaired barrier function represent a large and unmet need, especially among both the very young and increasing elderly population. These disorders include atopic dermatitis (7.3% of US adults), psoriasis (2-3% of US population), venous ulcers, stasis dermatitis and actinic keratosis. Barrier restoration with emollients is commonly used for many of these disorders, but is only partially effective. The fact that transepidermal water loss can be repaired without curing the inflammation suggests that specific biochemical abnormalities are not being addressed by simple emollients. In the cases of severe inflammatory disorders, such as atopic dermatitis and psoriasis, many biologics, targeting TNFα, IL-12, IL-17, IL-1β, and IL-4 have shown benefit, but these therapies are usually reserved for the 10% of most severe cases due to side effects and expense. The mainstay of less severe inflammatory skin disorders remains topical steroids, as it has been for the last 40 years. Other topicals, such as retinoids, vitamin D, and topical immunosuppressants have had less impact due to lesser efficacy and greater expense. Our central hypothesis is that solenopsin derivatives, which have ceramide-like properties, can alleviate inflammation, even in the face of infection. We test this hypothesis with novel ceramide analogs based on the ant venom alkaloid solenopsin, which are not metabolized into pro-inflammatory sphingosine-1 phosphate. It may be counterintuitive that a single signaling pathway could be inhibited to alleviate widely different disorders including psoriasis and atopic dermatitis caused by inflammation and bacterial colonization/infection. This speaks to the innovation of this protocol. Our preliminary data have demonstrated that topical solenopsin derivatives have efficacy in well-established preclinical models of atopic dermatitis (manuscript in preparation) and psoriasis 5. Moreover, these studies have independently identified interleukin-12 (IL-12) as elevated in response to topical solenopsin analogs. Given that IL-12 has also been implicated in infectious disease as well, it is therefore feasible that a single molecule could be used in the treatment of both inflammatory and infectious diseases of the skin. In addition, the burden of inflammatory and infectious skin disorders runs into tens of billions of dollars annually with some treatment of inflammatory disorders predisposing to infection (corticosteroids) and some anti-infectives having pro-inflammatory effects. Finally, a barrier restoration; IL-12 link could provide a common final pathway for the resolution of inflammatory and infectious skin conditions. Our discovery of IL-12 as a target of solenopsin analogs could be useful as novel adjuvants for vaccine development as well.

屏障功能受损的常见皮肤病代表了大量未满足的需求， 特别是在非常年轻和日益增长的老年人口中。这些病症包括 特应性皮炎（7.3%的美国成年人）、银屑病（2-3%的美国人口）、静脉溃疡、淤滞 皮炎和光化性角化病。使用润肤剂的屏障修复通常用于许多 这些疾病，但只有部分有效。经表皮水分流失可以修复的事实 没有治愈炎症表明，特定的生化异常并没有被 通过简单的润肤剂解决。在严重炎症性疾病的情况下，如特应性 皮炎和银屑病，许多靶向TNFα、IL-12、IL-17、IL-1β和IL-4的生物制剂已显示 这些疗法通常只用于10%的最严重病例， 和费用。不太严重的炎症性皮肤病的支柱仍然是局部类固醇，因为它 已经持续了40年其他外用药，如类维生素A、维生素D和外用药 免疫抑制剂由于功效较低和费用较高而影响较小。我们的中央 假设是具有神经酰胺样性质的solenopsin衍生物可以减轻 炎症，即使面对感染。我们用新的神经酰胺类似物来检验这一假设 基于蚂蚁毒液生物碱solenopsin，它不会被代谢成促炎物质， 鞘氨醇-1磷酸。 这可能是违反直觉的，一个单一的信号通路可以被抑制，以减轻广泛 不同的疾病，包括牛皮癣和特应性皮炎引起的炎症和细菌 定植/感染。这说明了该协议的创新性。我们的初步数据显示 证明了局部solenopsin衍生物在良好建立的临床前模型中具有功效， 特应性皮炎（手稿准备）和牛皮癣5.此外，这些研究 独立鉴定的白细胞介素-12（IL-12）响应于局部solenopsin类似物而升高。 鉴于IL-12也与感染性疾病有关，因此， 单分子可用于治疗皮肤的炎性和感染性疾病。 此外，炎症和感染性皮肤病的负担高达数百亿美元 每年对易感染的炎症性疾病进行一些治疗（皮质类固醇）， 一些具有促炎作用的抗感染药。最后，恢复屏障; IL-12的联系可以 为炎症和感染性皮肤病的解决提供了共同的最终途径。我们 发现IL-12作为solenopsin类似物的靶标可用作疫苗的新型佐剂 发展也是。