Serotonin 5-HT2A receptor inhibition of TNF-alpha pathways and atherosclerosis

血清素 5-HT2A 受体抑制 TNF-α 通路和动脉粥样硬化

基本信息

批准号：
8109955
负责人：
CHARLES D NICHOLS
金额：
$ 17.75万
依托单位：
LSU HEALTH SCIENCES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-15 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8109955
关键词：
Affect Aftercare Agonist American Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Arthritis Atherosclerosis Attention Biochemical Bipolar Disorder Cardiovascular system Cell Culture Techniques Cells Complex Coupled Crohn&apos s disease Development Disease Dose Drug Receptors Endothelial Cells Etanercept GTP-Binding Proteins Gene Expression Gene Expression Profiling Goals HTR2A gene Hour Immune response Inflammation Inflammatory Inhibitory Concentration 50 Injury Intercellular adhesion molecule 1 Interleukin-6 Irritable Bowel Syndrome Lead Ligands Link Mediating Mental Depression Modeling Molecular Molecular Biology Monoclonal Antibodies Mus NF-kappa B Neurodegenerative Disorders Non-Insulin-Dependent Diabetes Mellitus Nuclear Translocation Pathway interactions Pharmaceutical Preparations Physiological Primary Cell Cultures Process Psoriasis RNA Interference Rattus Receptor Activation Receptor Inhibition Rheumatoid Arthritis Rodent Schizophrenia Septicemia Serotonin Signal Pathway Signal Transduction Pathway Smooth Muscle TNF gene Testing Therapeutic Tissues Toxin Translating Tumor Necrosis Factor-alpha Vascular Cell Adhesion Molecule-1 adalimumab cell type cost cytokine human TNF protein in vivo inflammatory marker infliximab inhibitor/antagonist macrophage novel novel therapeutic intervention prevent receptor research study response serotonin receptor small molecule translational study

项目摘要

DESCRIPTION (provided by applicant): The overall goals of this project are to elucidate the molecular mechanisms underlying our recent discovery that serotonin 5-HT2A receptor activation super-potently inhibits TNFa-mediated inflammatory pathways, and to translate our findings to an animal model as a potential novel therapeutic approach to treat and/or prevent diseases like atherosclerosis that involve TNFa-mediated inflammation. TNF- a-mediated inflammatory pathways have been strongly implicated in a number of diseases including atherosclerosis, rheumatoid arthritis, psoriasis, type II diabetes, irritable bowel syndrome and Crohn's disease, and septicemia. Significantly, TNF-a and other cytokine induced inflammatory pathways also have been linked to psychiatric conditions such as depression and bipolar disorder, as well as schizophrenia, and neurodegenerative diseases. As such, inhibitors of TNF-a pro-inflammatory pathways represent potential therapeutics for each of these conditions. Currently, the only available therapeutic inhibitors of TNF-a pathways are monoclonal antibodies against TNF-a (infliximab and adalimumab) and soluble TNF-a receptor (etanercept), and the development of small molecules for this purpose is highly desirable. We have recently discovered that activation of 5-HT2A receptors in cardiovascular tissues including primary aortic smooth muscle, aortic endothelial, and macrophage cells by (R)-DOI, and likely additional 5-HT2A receptor agonists, represents a novel, and extraordinarily potent, therapeutic avenue to develop for the treatment of diseases and disorders involving TNF-a-mediated inflammation. Significantly, pro-inflammatory marker blockade occurs with IC50 drug levels of 10-20 picomolar. With the exception of a few natural toxins no current drugs or small molecule therapeutics demonstrate a comparable potency for any physiological effect. The experiments described in this proposal will elucidate the molecular signaling pathways linking activation of 5-HT2A receptors to inhibition of TNF- a-mediated pro-inflammatory process using molecular and biochemical approaches in primary cell culture experiments. Importantly, we will also perform translational studies in rodents to explore the anti-inflammatory effects of (R)-DOI in vivo. Results from these studies may lead to potential therapeutic strategies to not only prevent, but also treat existing pathological conditions like atherosclerosis via 5-HT2A receptor stimulation.

描述（由申请人提供）：该项目的总体目标是阐明我们最近发现的分子机制，即血清素5-HT2A受体激活超过抑制TNFA介导的炎症途径，并将我们的发现转化为动物模型作为一种潜在的新型治疗方法，例如治疗和预防疾病，将我们的发现转化为动物模型，以预防疾病的介绍，而这些方法涉及涉及的诱发方法。 TNF-A介导的炎症途径与多种疾病有着强烈的影响，包括动脉粥样硬化，类风湿关节炎，牛皮癣，II型糖尿病，肠易激综合症和克罗恩病，以及败血症。值得注意的是，TNF-A和其他细胞因子诱导的炎症途径也与精神病患者（如抑郁症和躁郁症）以及精神分裂症以及神经退行性疾病有关。因此，TNF-A促炎途径的抑制剂代表了每种疾病的潜在疗法。当前，TNF-A途径的唯一可用的治疗抑制剂是针对TNF-A（英夫利昔单抗和阿达木单抗）和可溶性TNF-A受体（Etanercept）的单克隆抗体，为此目的，小分子的发展是高度的。我们最近发现，通过（R）-DOI，包括原发性主动脉平滑肌，主动脉内皮和巨噬细胞在内的心血管组织中5-HT2A受体的激活，以及可能代表一种新颖的5-HT2A受体激动剂，代表一种新颖的，非常有效的治疗方法，可用于用于疾病和疾病的疾病和疾病。值得注意的是，IC50药物水平为10-20皮摩尔。除少数天然毒素外，没有当前药物或小分子疗法表现出可比的任何生理作用的效力。本提案中描述的实验将阐明将5-HT2A受体激活与使用分子和生化方法中原代细胞培养实验中的分子和生化方法抑制TNF- A介导的促炎过程的分子信号通路。重要的是，我们还将对啮齿动物进行翻译研究，以探索（R）-DOI在体内的抗炎作用。这些研究的结果可能导致潜在的治疗策略不仅可以预防，还可以通过5-HT2A受体刺激来治疗现有的病理状况。