Integrin receptor: A connecting link between skin and peripheral sensing neurons in atopic dermatitis

整合素受体：特应性皮炎皮肤和外周感觉神经元之间的连接纽带

• 批准号: 10440372
• 负责人: Santosh K. Mishra
• 金额: $ 21.26万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10440372
• 关键词: Address; Adolescent; Adrenal Cortex Hormones; Affect; Afferent Neurons; Allergens; Atopic Dermatitis; Binding; Brain; Calcipotriene; Cells; Cellular biology; Child; Chronic; Clinical; Complex; Cutaneous; Esthesia; Generations; Genetic; IL7R gene; Image; Immune response; Infectious Skin Diseases; Inflammatory; Integrin Binding; Integrin alphaVbeta3; Integrins; Knock-out; Ligands; Link; Liquid substance; Molecular; Motion; Mus; Nerve; Neural Pathways; Neurologic; Neuromodulator; Neurons; Neuropeptides; Pathway interactions; Patients; Peripheral; Pharmacology; Physiological; Population; Production; Proteins; Pruritus; Receptor Signaling; Research; Role; Secondary to; Signal Pathway; Signal Transduction; Skin; Spinal Cord; Spinal Ganglia; Stimulus; TSLP gene; Testing; Topical application; Up-Regulation; Viral; Wild Type Mouse; autocrine; calcium indicator; cell type; chronic itch; cytokine; effective therapy; in vivo; keratinocyte; mouse model; new therapeutic target; novel; paracrine; periostin; polypeptide; prospective; psychologic; public health relevance; receptor; response; saluretic; skin disorder; subcutaneous

Project Summary Atopic dermatitis is an inflammatory skin condition that affects an estimated 30% of the US population, mostly children and adolescents. Atopic dermatitis is characterized by chronically itchy skin that can weep clear fluid when scratched, and patients with atopic dermatitis are susceptible to bacterial, viral and fungal skin infection. There currently are no effective treatments for the chronic itch other than temporary symptomatic relief with topical applications (e.g. corticosteroids), and specific neurological pathways associated with the generation of chronic itch have not been elucidated. Here, we propose that CHRONIC ITCH, as occurs in Atopic Dermatitis, involves a novel signaling pathway that ends in release of NPPB by specific neurons in the DRG. Central to this pathway leading to chronic itch are four molecules: a) thymic stromal lymphopoietin (TSLP); b) PERIOSTIN c) the (αvβ3) integrin receptor on specific neurons of the DRG called transient receptor potential vanniloid-1 (TRPV1) neurons; and, as described above, d) natriuretic polypeptide precursor b (NPPB). The Specific Hypothesis to be addressed is propagation of chronic itch is is initiated by a Th2 type immune response in the skin related to atopic dermatitis. This causes localized release of the cytokine TSLP from skin keratinocytes (and perhaps other cell types in the skin) which then, in an autocrine/paracrine fashion, binds to these and other keratinocytes via the keratinocyte TSLP/IL7R-receptor complex. This binding activates the JAK-STAT pathway in the keratinocytes, leading to production and release of the protein PERIOSTIN. PERIOSTIN, released by these keratinocytes, then sets in motion the following itch circuit: Released PERIOSTIN binds to a PERIOSTIN - binding integrin receptor αvβ3 expressed on a subset of neurons in the dorsal root ganglia, called TRPV1 neurons. As a result of PERIOSTIN binding, these TRPV1 neurons then release the neuropeptide NPPB centrally in the spinal cord that in response sends itch signals to the brain. We will test this hypothesis through the following specific aims: Aim 1). To determine if TSLP binding to the specific TSLP receptor complex on keratinocytes provokes production and release of periostin through activation of the JAK-STAT pathway in these cells; Aim 2) To determine whether PERIOSTIN binds directly to the integrin receptor αvβ3 on TRPV1 neurons (NPPB/SST) in the DRG, and whether this generates an itch sensation in vivo; Aim 3) To demonstrate a direct role of PERIOSTIN and neuropeptide NPPB in the generation of chronic itch in vivo. This proposed research will identify fundamental mechanisms for neuronal responses during the generation of chronic itch secondary to inflammatory skin disease. PERIOSTIN, integrin receptor signaling, and/or NPPB – producing neurons may provide novel therapeutic targets to treat skin diseases manifested by chronic itch.

项目概要 特应性皮炎是一种炎症性皮肤病，影响了大约 30% 的美国人，其中大多数是 儿童和青少年特应性皮炎的特点是皮肤长期发痒，可流出透明液体。 特应性皮炎患者在抓伤时容易受到细菌、病毒和真菌的皮肤感染。 目前除了暂时缓解症状外，尚无针对慢性瘙痒的有效治疗方法。 局部应用（例如皮质类固醇），以及与产生相关的特定神经通路 慢性瘙痒尚未阐明，在此，我们提出慢性瘙痒，如特应性皮炎中所发生的那样。 涉及一种新的信号传导途径，最终由 DRG 中的特定神经元释放 NPPB。 导致慢性瘙痒的途径有四种分子：a) 胸腺基质淋巴细胞生成素 (TSLP)； Periostin c) DRG 特定神经元上的 (αvβ3) 整合素受体，称为瞬时受体电位 vanniloid-1 (TRPV1) 神经元；以及如上所述，d) 利尿钠多肽前体 b (NPPB)。 要解决的具体假设是慢性瘙痒的传播是由 Th2 型免疫反应引发的 与特应性皮炎相关的皮肤中，这会导致皮肤角质形成细胞局部释放细胞因子 TSLP。 （也许还有皮肤中的其他细胞类型），然后以自分泌/旁分泌的方式与这些和其他细胞结合 通过角质形成细胞 TSLP/IL7R 受体复合物，这种结合激活 JAK-STAT 通路。 在角质形成细胞中，导致骨膜素蛋白的产生和释放，该蛋白由骨膜素释放。 然后，这些角质形成细胞启动以下瘙痒回路：释放的佩里奥汀与佩里奥汀结合 - 结合整合素受体 αvβ3 在背根神经节的一部分神经元上表达，称为 TRPV1 由于 Periostin 结合，这些 TRPV1 神经元随后释放神经肽 NPPB。 位于脊髓的中央，它会向大脑发送瘙痒信号，我们将通过以下方式验证这一假设。 具体目标如下： 目标 1) 确定 TSLP 是否与特定 TSLP 受体复合物结合。 角质形成细胞通过激活这些细胞中的 JAK-STAT 通路来激发骨膜素的产生和释放 细胞；目标 2) 确定 PERIOSTIN 是否直接与 TRPV1 神经元上的整合素受体 αvβ3 结合 (NPPB/SST) 在 DRG 中，以及这是否会在体内产生瘙痒感 目的 3) 证明直接作用； 佩里奥汀和神经肽 NPPB 在体内产生慢性瘙痒中的作用。 确定继发性慢性瘙痒产生过程中神经反应的基本机制 炎症性皮肤病、整合素受体信号传导和/或产生 NPPB 的神经元可能 为治疗以慢性瘙痒为表现的皮肤病提供新的治疗靶点。