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着巨大且未得到满足的需求， 尤其是在非常年轻和不断增加的老年人口中，这些疾病包括。 特应性皮炎（占美国成年人的 7.3%）、牛皮癣（占美国人口的 2-3%）、静脉性溃疡、瘀血 皮炎和光化性角化病通常使用润肤剂修复屏障。 这些疾病，但仅部分有效，事实是经皮水分流失可以修复。 没有治愈炎症表明特定的生化异常没有得到解决 在严重的炎症性疾病（例如特应性过敏）的情况下，可以通过简单的润肤剂来解决。 皮炎和牛皮癣，许多针对 TNFα、IL-12、IL-17、IL-1β 和 IL-4 的生物制剂已被证明 好处，但由于副作用，这些疗法通常只用于 10% 的最严重病例 不太严重的炎症性皮肤病的主要药物仍然是外用类固醇，因为它 过去 40 年来一直在使用其他外用药物，例如类视黄醇、维生素 D 和外用药物。 由于疗效较差且费用较高，免疫抑制剂的影响较小。 假设具有神经酰胺样特性的 Solenopsin 衍生物可以缓解 即使面对感染，我们也用新型神经酰胺类似物测试了这一假设。 基于蚂蚁毒生物碱 Solenopsin，不会代谢为促炎物质 1-磷酸鞘氨醇。 抑制单一信号通路可以广泛缓解症状可能是违反直觉的。 由炎症和细菌引起的不同疾病，包括牛皮癣和特应性皮炎 我们的初步数据表明了定植/感染。 局部 Solenopsin 衍生物已在成熟的临床前模型中证明了功效 特应性皮炎（手稿正在准备中）和牛皮癣 5. 此外，这些研究还 独立鉴定白细胞介素 12 (IL-12) 因局部 Solenopsin 类似物而升高。 鉴于 IL-12 也与传染病有关，因此有可能 单分子可用于治疗皮肤炎症和感染性疾病。 此外，炎症和传染性皮肤病的负担高达数百亿美元 每年进行一些易感染炎症性疾病的治疗（皮质类固醇）和 最后，一些具有促炎作用的抗感染药物可以恢复IL-12的连接； 为解决炎症和感染性皮肤病提供共同的最终途径。 发现 IL-12 作为 solenopsin 类似物的靶标，可用作新型疫苗佐剂 发展也是如此。