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.

障碍功能受损的常见皮肤疾病代表了巨大而未满足的需求， 尤其是在很小的年轻人和年龄较大的人群中。这些疾病包括 特应性皮炎（美国成年人的7.3％），牛皮癣（占美国人群的2-3％），静脉溃疡，停滞 皮炎和放映的角化病。润肤剂的屏障修复通常用于许多 这些疾病，但仅是部分有效的。可以修复旋转皮肤水分的事实 没有使炎症表明特定的生化异常不是 由简单的润肤剂解决。在严重炎症性疾病的情况下，例如特应性疾病 皮肤炎和牛皮癣，许多生物制剂，靶向TNFα，IL-12，IL-17，IL-1β和IL-4 好处，但由于副作用，这些疗法通常保留给最严重的10％ 和费用。炎症性皮肤疾病不太严重的主要类固醇仍然是局部类固醇 过去40年。其他局部情况，例如类维生素，维生素D和局部 由于效率较低和费用较高，免疫抑制剂的影响较小。我们的中心 假设是具有类似神经酰胺的特性的溶烯蛋白衍生物可以减轻 即使面对感染，炎症也是如此。我们用新型的神经酰胺类似物检验了这一假设 基于蚂蚁毒液生物碱螺旋杆菌素，未代谢成促炎症 鞘氨醇1磷酸盐。 可以抑制单个信号通路以缓解广泛的信号通路可能是违反直觉的 不同的疾病，包括牛皮癣和特应性皮炎，由感染和细菌引起 定植/感染。这说明了该协议的创新。我们的初步数据 证明局部螺纹素衍生物在完善的临床前模型中具有有效性 特应性皮炎（制备中的手稿）和牛皮癣5。此外，这些研究具有 独立鉴定的白介素12（IL-12）响应局部电载蛋白类似物而升高。 鉴于IL-12也与传染病有关，因此，可行的是 单分子可用于治疗皮肤的炎症和传染病。 此外，炎症和感染性皮肤疾病的伯恩（Burnen）占数万美元 每年对炎症性疾病的某种治疗易于感染（皮质类固醇）和 一些具有促炎作用的抗感染物。最后，障碍恢复； IL-12链接可以 为解决炎症和感染性皮肤状况的分辨提供了通用的最终途径。我们的 发现IL-12作为螺诺蛋白类似物的靶标可以作为疫苗的新调节器有用 发展也。