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.

项目摘要 特应性皮炎是一种炎症性皮肤病，估计影响30%的美国人口，主要是 儿童和青少年。特应性皮炎的特点是长期发痒的皮肤，可以渗出明确的液体 特应性皮炎患者易受细菌、病毒和真菌的皮肤感染。 目前，除了暂时缓解症状外，没有有效的治疗慢性瘙痒的方法。 局部应用（例如皮质类固醇），以及与生成 慢性瘙痒尚未阐明。在这里，我们提出慢性瘙痒，如发生在特应性皮炎， 涉及一种新的信号传导途径，其通过DRG中的特定神经元以NPPB的释放结束。的核心 这种导致慢性瘙痒的途径是四种分子：a）胸腺基质淋巴细胞生成素（TSLP）; B） 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（TRPV 1）神经元;和，如上所述，d）利钠多肽前体B（NPP B）。的 要解决的具体假设是慢性瘙痒的传播是由Th 2型免疫应答启动的 与特应性皮炎有关的皮肤。这导致细胞因子TSLP从皮肤角质形成细胞局部释放 (and可能是皮肤中的其他细胞类型），然后以自分泌/旁分泌的方式结合这些和其他细胞类型， 通过角质形成细胞TSLP/IL 7 R-受体复合物对角质形成细胞的作用。这种结合激活JAK-STAT途径 在角质形成细胞中，导致蛋白PERIOSTIN的产生和释放。PERIOSTIN，由 这些角质形成细胞，然后启动以下瘙痒回路：释放的PERIOSTIN结合PERIOSTIN - 结合整合素受体αvβ3在背根神经节的一个神经元亚群上表达，称为TRPV 1 神经元作为PERIOSTIN结合的结果，这些TRPV 1神经元然后释放神经肽NPPB 在脊髓的中央，作为回应，向大脑发送瘙痒信号。我们将通过以下方式来验证这一假设： 具体目标如下：目标1）。为了确定TSLP是否与细胞表面的特异性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途径引起骨膜蛋白的产生和释放。 目的2）确定PERIOSTIN是否直接结合TRPV 1神经元上的整合素受体αvβ3 (NPPB/SST）在背根神经节中的作用，以及这是否会在体内产生瘙痒感;目的3）证明直接的 PERIOSTIN和神经肽NPPB在体内慢性瘙痒产生中的作用。这项研究将 确定在继发于慢性瘙痒的产生过程中神经元反应的基本机制， 炎症性皮肤病。PERIOSTIN、整联蛋白受体信号传导和/或NPPB产生神经元可 提供新的治疗靶点以治疗表现为慢性瘙痒的皮肤病。