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

描述(申请人提供)：这个项目的总体目标是阐明我们最近发现的5-HT2A受体激活超强抑制TNFa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，作为一种潜在的新的治疗方法来治疗和/或预防涉及TNFa介导的炎症的动脉粥样硬化等疾病。肿瘤坏死因子-α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、银屑病、II型糖尿病、肠易激综合征和克罗恩病以及败血症。值得注意的是，肿瘤坏死因子-α和其他细胞因子诱导的炎症途径也与精神疾病有关，如抑郁症和双相情感障碍，以及精神分裂症和神经退行性疾病。因此，肿瘤坏死因子-a的抑制剂代表了每种疾病的潜在治疗方法。目前，仅有的抗肿瘤坏死因子-α途径的治疗抑制剂是抗肿瘤坏死因子-α的单抗(英夫利昔单抗和阿达莫单抗)和可溶性肿瘤坏死因子-α受体(依那西普)，开发用于此目的的小分子是非常可取的。我们最近发现，(R)-DOI激活心血管组织中的5-HT2A受体，包括主动脉平滑肌、主动脉内皮细胞和巨噬细胞，以及可能的其他5-HT2A受体激动剂，代表了一种新的、非常有效的治疗途径，可用于治疗与肿瘤坏死因子-a介导的炎症有关的疾病。值得注意的是，促炎标志物的阻断发生在IC50药物水平为10-20微微克分子时。除了少数几种天然毒素外，目前的药物或小分子疗法都没有显示出任何生理效应的同等效力。本方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受体的激活与抑制肿瘤坏死因子-a介导的促炎过程联系起来的分子信号通路。重要的是，我们还将在啮齿动物身上进行翻译研究，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，还可以通过刺激5-HT2A受体来治疗现有的病理情况，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.