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

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5-羟色胺5-HT2A受体激活超强抑制tnfa介导的炎症途径的分子机制，并将我们的发现转化为动物模型，作为治疗和/或预防涉及tnfa介导炎症的动脉粥样硬化等疾病的潜在新治疗方法。TNF- a介导的炎症通路与许多疾病密切相关，包括动脉粥样硬化、类风湿性关节炎、牛皮癣、II型糖尿病、肠易激综合征、克罗恩病和败血症。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疾病有关，如抑郁症、双相情感障碍、精神分裂症和神经退行性疾病。因此，TNF-a促炎途径的抑制剂代表了这些疾病的潜在治疗方法。目前，唯一可用的治疗性TNF-a通路抑制剂是针对TNF-a的单克隆抗体（英夫利昔单抗和阿达木单抗）和可溶性TNF-a受体（依那西普），为此目的开发小分子是非常可取的。我们最近发现，通过(R)-DOI激活心血管组织中的5-HT2A受体，包括原发性主动脉平滑肌、主动脉内皮细胞和巨噬细胞，以及可能额外的5-HT2A受体激动剂，代表了一种新的、非常有效的治疗途径，用于治疗涉及tnf -a介导的炎症的疾病和失调。值得注意的是，促炎标志物阻断发生在IC50药物水平为10-20皮摩尔。除少数天然毒素外，目前没有任何药物或小分子疗法在任何生理效应方面表现出可比的效力。本提案中描述的实验将阐明在原代细胞培养实验中使用分子和生化方法将5-HT2A受体的激活与TNF- a介导的促炎过程的抑制联系起来的分子信号通路。重要的是，我们还将在啮齿动物中进行转化研究，以探索(R)-DOI在体内的抗炎作用。这些研究的结果可能会导致潜在的治疗策略，不仅可以预防，而且可以通过5-HT2A受体刺激治疗动脉粥样硬化等现有病理状况。

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.