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: 10650321
• 负责人: Santosh K. Mishra
• 金额: $ 33.87万
• 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/10650321
• 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; Predisposition; Production; Proteins; Pruritus; Receptor Signaling; Research; Role; Secondary to; Signal Pathway; Signal Transduction; Skin; Spinal Cord; Spinal Ganglia; Stimulus; TRPV1 gene; 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; transmission process

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，影响美国人群的30％，主要是 儿童和青少年。特应性皮炎的特征是长期发痒的皮肤，可以哭泣清晰的液体 划伤时，特应性皮炎的患者容易受到细菌，病毒和真菌皮肤感染的影响。 除了暂时的症状缓解外，目前尚无慢性瘙痒的有效治疗方法 局部应用（例如皮质类固醇）和与产生有关的特定神经系统途径 尚未阐明慢性瘙痒。在这里，我们建议在特应性皮炎中发生的慢性瘙痒， 涉及一种新型的信号通路，该通路在DRG中特定的神经元释放为NPPB结束。中心 导致慢性瘙痒的这种途径是四个分子：a）胸腺基质淋巴细胞素（TSLP）； b） 骨膜素C）在DRG的特定神经元上的（αVβ3）称为瞬时受体电位的受体 Vanniloid-1（TRPV1）神经元；如上所述，d）纳特里脲多肽前体B（NPPB）。 要解决的特定假设是慢性瘙痒的传播是由Th2型免疫反应引发的 在与特应性皮炎有关的皮肤中。这导致皮肤角质形成细胞的细胞因子TSLP局部释放 （也许是皮肤中的其他细胞类型）然后，它以自分泌/旁分泌方式与这些和其他细胞的方式结合 角质形成细胞通过角质形成细胞TSLP/IL7R受体复合物。这种绑定激活了jak-stat途径 在角质形成细胞中，导致蛋白质骨膜素的产生和释放。骨膜，发行 这些角质形成细胞，然后启动以下瘙痒电路：释放的骨膜结合到骨膜蛋白 - 结合整合素受体αVβ3在背根神经节中的神经元子集中表达，称为TRPV1 神经元。由于骨膜蛋白结合，这些TRPV1神经元然后释放神经肽NPPB 以响应将瘙痒信号传递到大脑的脊髓中心。我们将通过 以下特定目的：目标1）。确定TSLP是否与特定的TSLP受体复合物结合 角质形成细胞通过激活Jak-Stat途径在这些中激发和释放时期 细胞；目标2）确定骨膜素是否直接与TRPV1神经元上整联蛋白受体αVβ3结合 （nppb/sst）在DRG中，以及这是否会在体内产生瘙痒感；目标3）表现直接 骨膜素和神经肽NPPB在体内产生慢性瘙痒中的作用。这项拟议的研究将 确定在继发于慢性瘙痒期间神经元反应的基本机制 炎症性皮肤病。骨膜蛋白，整联蛋白受体信号传导和/或NPPB - 产生神经元可能 提供新型的热靶标，以治疗由慢性瘙痒所表现出的皮肤疾病。

项目成果

Brain Natriuretic Peptide Exerts Inflammation and Peripheral Itch in a Mouse Model of Atopic Dermatitis.

脑利钠肽在特应性皮炎小鼠模型中引起炎症和外周瘙痒。

• DOI: 10.1016/j.jid.2023.09.273
• 发表时间: 2024
• 期刊: The Journal of investigative dermatology
• 作者: Wheeler,JoshuaJ;Williams,Nidha;Yu,Junho;Mishra,SantoshK
• 通讯作者: Mishra,SantoshK

The Role of CNTNAP2 in Itch Sensation.

• DOI: 10.1016/j.jid.2021.07.152
• 发表时间: 2022-01
• 期刊: The Journal of investigative dermatology
• 作者: Mishra SK

Role of TRP ion channels in pruritus.

• DOI: 10.1016/j.neulet.2021.136379
• 发表时间: 2022-01-18
• 期刊: Neuroscience letters
• 影响因子: 2.5
• 作者: Shirolkar P;Mishra SK
• 通讯作者: Mishra SK