Sensory Ion Channel Modulation by Bioactive Lipids

我们目前的研究集中在研究生物活性脂类调节功能的机制。 血管和感觉瞬时受体电位(Trp)离子通道。色氨酸离子通道的成员 亚家族参与多种生理过程，包括温度、化学物质和有害刺激 检测，以及渗透调节和神经和血管功能。色氨酸通道功能障碍是其基础 不同的病理生理条件，如疼痛过敏、周围神经病变(例如，在 糖尿病)、炎症、高血压、神经疾病(如小脑性共济失调)和肾脏疾病。自.以来 色氨酸通道在健康和疾病中起着至关重要的作用，激动剂和拮抗剂面临着许多挑战 由于它们的副作用，在临床试验中必须克服。我们设想了微调TRP的新战略 在保持生理作用的同时，通道的功能可能会避开 医药类药物。在过去的五年中，我们深入了解了 多不饱和脂肪酸(PUFAs)、肌醇磷脂和甘油调节TRPV4的功能， TRPV1和TRPC6。结合不同的体外和体内方法，我们的目标是描绘 ω-3多不饱和脂肪酸增强TRPV4功能的机制及其改善通道介导功能的可能性 血管功能障碍。此外，我们将重点确定TRPV1 C-末端的结构基础 结构域与质膜的相互作用以及TRPC通道对生物活性脂类的内在敏感性。 综上所述，我们提议的工作有望提供分子框架，以便理解 生物活性脂类微调血管和神经系统中的色氨酸通道功能。这些发现将反过来， 促进制定针对Trp通道的策略，而不破坏正常生理。

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.