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Targeting TNFR2 Pathways in Psoriatic Diseases

银屑病疾病中的靶向 TNFR2 通路

基本信息

批准号：
10208727
负责人：
Unnikrishnan M Chandrasekharan
金额：
$ 34.36万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-08 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10208727
关键词：
Acute Adverse effects Adverse event Antibodies Arginine Binding Biological Products Blood Cell Surface Receptors Cells Chemicals Chronic Clinical Data Cultured Cells Data Defect Development Disease Early treatment Epidermis Genes Genetic Markers Genetic Polymorphism Goals Host Defense Human Immune In Vitro Infection Inflammation Inflammatory Inflammatory Response Knock-out Knockout Mice Lead Life Link Lysine Malignant Neoplasms Mediating Methionine Modification Molecular Monoubiquitination Morphology Mouse Strains Mus Myosin ATPase Nucleotides Pathogenesis Pathology Pathway interactions Patients Penetrance Pharmaceutical Preparations Post-Translational Protein Processing Protein-Arginine N-Methyltransferase Psoriasis Psoriatic Arthritis Reporting Restriction Fragment Length Polymorphism Analysis Role Safety Signal Transduction Skin TNF gene TNFRSF1A gene TNFRSF1B gene Tamoxifen Testing Therapeutic Effect Time Tissues Variant base biobank chemical genetics cytokine gain of function gene induction genetic approach genetic variant improved in vitro activity inhibitor/antagonist mouse model mutant neutralizing antibody new therapeutic target non-muscle myosin novel patient subsets personalized approach preclinical study predict responsiveness prevent promoter receptor reconstitution recruit research clinical testing side effect therapeutic evaluation therapy adverse effect transcription factor

项目摘要

Project Summary Tumor necrosis factor-a (TNF), a proinflammatory cytokine, functions by activating two cell surface receptors, TNFR1 and TNFR2. Current commercially approved anti-TNF therapies neutralize TNF thus preventing both TNFR1 and TNFR2 activation. Although these anti-TNF agents have demonstrated great efficacy in treating immune-mediated diseases, including psoriasis and psoriatic arthritis, potentially life-threatening infections and malignancies are associated with long-term use. Preclinical studies showed these unintended effects are due to TNFR1, not TNFR2 inactivation. Further, a subset of patients do not adequately respond to anti-TNF therapy over time. Unfortunately, no clinical test to predict responsiveness to the anti-TNF therapy is available. Our long-term goal is to demonstrate that selective inactivation of TNFR2 pathways with chemical inhibitors is effective in treating immune-mediated diseases with reduced adverse effects. Secondly, our studies may link a genetic variant of TNFR2 (TNFR2-M196R) to the reduced responsiveness to anti-TNF drugs. Our preliminary results show global knockout of TNFR2 is sufficient to inhibit psoriatic inflammation in a mouse model. Thus, selectively blocking TNFR2 pathways may ameliorate psoriasis and potentially reduce TNFR1 inhibition-related adverse events. Previously we and others, demonstrated that PRMT5 (protein arginine methyltransferase 5)-mediated arginine dimethylation on specific transcription factors is critical for TNF-mediated inflammatory gene induction. Our recent results show that PRMT5 activation is downstream of TNFR2, not TNFR1, and that a PRMT5-specific chemical inhibitor, EPZ015666 (EPZ), reduces psoriatic inflammation in mice. Earlier, we also demonstrated that non-muscle myosin (myosin) is an “off-switch” of TNFR2 signaling by binding to its cytosolic signaling domain. We now discovered that unlike TNFR2, TNFR2-M196R fails to bind to myosin in cultured cells or in cells isolated from human blood and show constitutive proinflammatory activity in vitro. Based on our findings and preliminary data we hypothesize that inactivation of TNFR2 or chemical inhibition of PRMT5 will ameliorate psoriatic inflammation. Further, a defect in myosin binding to the TNFR2 genetic variant, TNFR2-M196R, causes a constitutive, TNF-independent activity, thus leading to reduced responsiveness in patients treated with anti-TNF agents. We will test this hypothesis in two aims. In Aim 1, using two psoriasis mouse models, we will investigate the mechanisms underlying TNFR2 activity on psoriatic pathogenesis. We will also study the mechanistic basis of the constitutive activities of TNFR2-M196R in cultured cells. Furthermore, will test retrospectively if this polymorphism would predict responsiveness to anti-TNF agents in patients with psoriatic diseases. In Aim 2, using in vitro approaches we will investigate the mechanistic role of PRMT5 post-translational modifications on TNFR2 function. Further, using chemical and genetic approaches we will test the effect of PRMT5 inhibition on psoriasis pathogenesis. Our approach, blocking TNFR2 signaling and leaving TNFR1 activity intact, is novel and may lead to improved safety for the long-term treatment of chronic immune-mediated diseases. Further, our study may help to predict inadequate responders to anti-TNF therapies early on, allowing more personalized approach in treating psoriatic diseases.

项目总结