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: 10209759
• 负责人: Santosh K. Mishra
• 金额: $ 33.44万
• 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/10209759
• 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.

项目总结