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疾病，估计影响30%的美国人口，主要是 儿童和青少年。特应性皮炎的特征是皮肤慢性瘙痒，可以流出透明的液体。 当被抓伤时，特应性皮炎患者容易受到细菌、病毒和真菌皮肤的感染。 除了暂时缓解症状外，目前还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)，以及与产生 慢性瘙痒还没有被阐明。在这里，我们提出慢性瘙痒，就像特应性皮炎一样， 涉及一种新的信号通路，最终由DRG中的特定神经元释放NPPB。中心到 导致慢性瘙痒的途径有四个分子：a)胸腺间质淋巴生成素(TSLP)；b) Periostin c)背根神经节特定神经元上的(αvβ3)整合素受体，称为瞬时受体电位 Vannilid-1(TRPV1)神经元；以及，如上所述，d)利钠多肽前体b(NPPB)。这个 需要解决的特定假设是慢性瘙痒的传播是由Th2型免疫反应启动的 在皮肤中与特应性皮炎有关。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类型的细胞)，然后以自分泌/旁分泌的方式与这些和其他细胞结合 角质形成细胞通过角质形成细胞TSLP/IL7R-受体复合体。这种结合激活了JAK-STAT通路 在角质形成细胞中，导致蛋白质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与Periostin结合 -结合整合素受体αvβ3表达于背根神经节的神经元亚群，称为TRPV1 神经元。由于Periostin的结合，这些TRPV1神经元随后释放神经肽NPPB 在脊髓的中央，作为回应，它向大脑发送瘙痒信号。我们将通过以下方式检验这一假设 具体目标如下：目标1)。确定TSLP是否与特定的TSLP受体复合体结合 角质形成细胞通过激活JAK-STAT通路刺激Periostin的产生和释放 目的2)确定Periostin是否与TRPV1神经元上的整合素受体αvβ3直接结合 (NPPB/SST)在DRG中，以及这是否在体内产生瘙痒感觉；目的3)展示直接的 Periostin和神经肽NPPB在体内慢性瘙痒发生中的作用。这项拟议的研究将 确定继发性慢性瘙痒发生过程中神经元反应的基本机制 炎症性皮肤病。Periostin、整合素受体信号传递和/或NPPB产生的神经元可能 为治疗以慢性瘙痒为表现的皮肤病提供新的治疗靶点。

项目成果

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

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