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

描述（由申请人提供）：本项目的总体目标是阐明我们最近发现的5-羟色胺5-HT 2A受体激活超强抑制TNF α介导的炎症通路的分子机制，并将我们的发现转化为动物模型，作为治疗和/或预防涉及TNF α介导的炎症的疾病（如动脉粥样硬化）的潜在新治疗方法。TNF-α介导的炎症途径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、肠易激综合征和克罗恩病以及败血症。重要的是，TNF-α和其他细胞因子诱导的炎性途径也与精神病症如抑郁症和双相情感障碍以及精神分裂症和神经退行性疾病有关。因此，TNF-α促炎途径的抑制剂代表了这些病症中的每一种的潜在治疗剂。目前，唯一可用的TNF-α途径的治疗性抑制剂是针对TNF-α的单克隆抗体（英夫利昔单抗和阿达木单抗）和可溶性TNF-α受体（依那西普），并且高度期望开发用于该目的的小分子。我们最近发现，通过（R）-DOI和可能的另外的5-HT 2A受体激动剂激活心血管组织（包括原代主动脉平滑肌、主动脉内皮和巨噬细胞）中的5-HT 2A受体，代表了开发用于治疗涉及TNF-α介导的炎症的疾病和病症的新的且非常有效的治疗途径。值得注意的是，促炎标记物阻断发生在10-20皮摩尔的IC 50药物水平。除了少数天然毒素外，目前没有药物或小分子治疗剂表现出任何生理作用的可比效力。本提案中描述的实验将在原代细胞培养实验中使用分子和生物化学方法阐明将5-HT 2A受体的活化与TNF-α介导的促炎过程的抑制联系起来的分子信号传导途径。重要的是，我们还将在啮齿动物中进行翻译研究，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，而且可以通过5-HT 2A受体刺激治疗现有的病理条件，如动脉粥样硬化。

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.