Sensory Ion Channel Modulation by Bioactive Lipids

我们目前的研究重点是研究生物活性脂质调节功能的机制 血管和感觉瞬时受体电位 (TRP) 离子通道。 TRP离子通道成员 亚科参与各种生理过程，包括温度、化学和有害刺激 检测以及渗透调节以及神经元和血管功能。 TRP 通道功能障碍是造成 不同的病理生理状况，例如疼痛过敏、周围神经病变（例如，在 糖尿病）、炎症、高血压、神经系统疾病（例如小脑性共济失调）和肾脏疾病。自从 TRP通道在健康和疾病中发挥着关键作用，激动剂和拮抗剂面临着许多挑战 由于其副作用，在临床试验期间必须克服。我们设想微调 TRP 的新策略 通道功能在保持其生理作用的同时，可能会避免不良的副作用 药品。在过去的五年里，我们深入了解了其中的机制。 多不饱和脂肪酸 (PUFA)、磷酸肌醇脂质和二酰甘油调节 TRPV4 的功能， 分别为 TRPV1 和 TRPC6。结合各种体外和体内方法，我们的目标是描述 ω-3 PUFA 增加 TRPV4 功能的机制及其改善通道介导的潜力 血管功能障碍。此外，我们将重点确定 TRPV1 C 端的结构基础 域与质膜的相互作用以及 TRPC 通道对生物活性脂质的内在敏感性。 总而言之，我们提出的工作预计将为理解如何 生物活性脂质可微调血管和神经系统中的 TRP 通道功能。这些发现反过来将 促进针对 TRP 通道的策略的开发，而不破坏正常的生理机能。

Our current research focuses on investigating the mechanisms by which bioactive lipids modulate the function of vascular and sensory transient receptor potential (TRP) ion channels. Members of the TRP ion channel subfamily are involved in various physiological processes, including temperature, chemical, and noxious stimuli detection, as well as osmoregulation and neuronal and vascular function. TRP channel dysfunction underlies different pathophysiological conditions such as pain hypersensitivity, peripheral neuropathies (e.g., during diabetes), inflammation, hypertension, neurological disorders (e.g., cerebellar ataxia), and kidney disease. Since TRP channels play critical roles in health and disease, there are many challenges that agonists and antagonists must overcome during clinical trials due to their side effects. We envision that new strategies that fine-tune TRP channels function, while maintaining their physiological roles, might circumvent undesired side effects of pharmaceutical drugs. In the past five years, we have gained insights into the mechanisms by which polyunsaturated fatty acids (PUFAs), phosphoinositide lipids, and diacylglycerol regulate the function of TRPV4, TRPV1, and TRPC6, respectively. Combining various in vitro and in vivo approaches, we aim to depict the mechanism by which ω-3 PUFAs increase TRPV4 function and its potential for ameliorating channel-mediated vascular dysfunction. Moreover, we will focus on determining the structural bases of the TRPV1 C-terminal domain interaction with the plasma membrane and the intrinsic sensitivity of TRPC channels to bioactive lipids. Taken together, our proposed work is expected to provide the molecular framework for understanding how bioactive lipids fine-tune TRP channel function in the vascular and nervous systems. These findings will, in turn, facilitate the development of strategies to target TRP channels, without disrupting normal physiology.