P2X7 Receptor Splice Variants in Psoriasis Pathophysiology

银屑病病理生理学中的 P2X7 受体剪接变异体

• 批准号: 10398805
• 负责人: ALICIA R MATHERS
• 金额: $ 17.27万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10398805
• 关键词: Acute; Address; Adverse effects; Affect; Alternative Splicing; Apoptosis; Autoimmune Diseases; Biological; Biological Products; Cell Proliferation; Cell Survival; Chronic; Chronic small plaque psoriasis; Cutaneous; Data; Dermatitis; Development; Disasters; Effectiveness; Functional disorder; Future; Goals; Human; Immune response; Immunologics; Immunosuppression; Immunosuppressive Agents; In Vitro; Infection; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Interleukin-17; Ion Channel; Lead; Lesion; Link; Maintenance; Malignant Neoplasms; Mediator of activation protein; Methods; Modeling; Morbidity - disease rate; Mus; Outcome; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Persons; Population; Predisposition; Protein Isoforms; Psoriasiform Dermatitis; Psoriasis; Publishing; RNA Splicing; Receptor Signaling; Relapse; Resolution; Role; Signal Transduction; Skin; Testing; Therapeutic; Variant; cost; cytotoxicity; differential expression; extracellular; human model; humanized mouse; improved; in vivo; insight; interleukin-23; knowledge base; mouse model; new therapeutic target; novel; novel therapeutics; overexpression; pre-clinical; preclinical study; receptor; response; skin disorder

Psoriasis is a cutaneous autoimmune disease that affects as many as 125 million people worldwide. Current therapeutics for psoriasis include systemic acting immuno-suppressive drugs for which long-term adverse effects remain a concern. Thus, a better understanding of psoriasis pathophysiology and cutaneous inflammation is pivotal for the development of new therapeutics. There are approximately 9000 alternatively spliced variants differentially expressed in psoriasis. However, pathways that lead to alternatively spliced isoforms remain to be identified in psoriasis patients. In this regard, the alternatively spliced purinergic P2X7 receptor variant B (P2X7RB) is highly expressed in human psoriatic lesions; whereas the canonical P2X7R variant A (P2X7RA) is expressed comparably in lesional, non-lesional, and normal human skin. Extracellular ATP, an alarmin, signaling through the P2X7R is a particularly appealing therapeutic pathway. P2X7RA stimulation leads to inflammasome and NF-κB activation and induction of the IL-23/IL-17 axis, which are psoriasis susceptibility pathways. Thus, upstream P2X7R signaling links early inflammatory triggers with psoriasis susceptibility factors. In fact, results from our ongoing studies have revealed that signaling through the P2X7RA leads to the development of psoriatic dermatitis in multiple murine and human models of psoriasis; however this is only an acute response that resolves within 6 days. Conversely, the P2X7RB variant lacks the intracellular C-terminus that confers P2X7R signaling cytotoxicity and therefore we hypothesize limits the ability of P2X7R signaling to induce inflammatory resolution. Signaling via the P2X7RB enhances cellular proliferation, decreases ATP-induced apoptosis, and in heterotrimers with P2X7RA, P2X7RB potentiates inflammatory responses. To understand the role of these variants in psoriasis pathophysiology, it will be necessary to determine which variants are crucial for the induction and maintenance of psoriasis. Our central hypothesis is that cutaneous overexpression of the P2X7RB variant has a prominent role in the pathophysiology of psoriasis. The overarching goal of this proposal is to establish the mechanisms that induce P2X7RB overexpression and to understand the involvement of P2X7RB signaling in psoriasis. To this end, we have developed the following specific aims: Aim 1: Establish the alternative splicing pathways that lead to P2X7RB variant expression and Aim 2: Determine the role of P2X7RB in psoriasis pathogenesis. P2X7RA is an early upstream mediator of many biological and immunological pathways, whose blockade could be an immunological disaster. Importantly, our findings herein, will be exploited for novel psoriasis therapies by precisely targeting only the alternative splicing pathways leading to the overexpression of P2X7RB, while retaining canonical P2X7RA and the patient immunologically active.

牛皮癣是一种皮肤自身免疫性疾病，影响全球多达1.25亿人。当前的