Sensory Ion Channel Modulation by Bioactive Lipids

生物活性脂质对感觉离子通道的调节

• 批准号: 10978347
• 负责人: Julio F Cordero-Morales
• 金额: $ 33.66万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10978347
• 关键词: Sensory; Ion; Channel; Modulation; Bioactive

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.

我们目前的研究重点是探讨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 亚家族参与各种生理过程，包括温度、化学和伤害性刺激 检测，以及神经元调节和神经元和血管功能。TRP通道功能障碍是 不同的病理生理状况，例如疼痛超敏反应、周围神经病（例如，期间 糖尿病）、炎症、高血压、神经障碍（例如，小脑共济失调）和肾脏疾病。以来 TRP通道在健康和疾病中起着关键作用，激动剂和拮抗剂的研究面临着许多挑战， 在临床试验中必须克服它们的副作用。我们设想，微调TRP的新策略 通道功能，同时保持其生理作用，可能会避免不希望的副作用， 药品在过去的五年里，我们已经深入了解了 多不饱和脂肪酸（PUFA）、磷酸肌醇脂质和二酰基甘油调节TRPV 4的功能， TRPV 1和TRPC 6。结合各种体外和体内方法，我们的目标是描述 ω-3 PUFAs增加TRPV 4功能的机制及其改善通道介导的 血管功能障碍此外，我们将重点确定TRPV 1 C-末端的结构基础， 结构域与质膜的相互作用以及TRPC通道对生物活性脂质的内在敏感性。 总的来说，我们提出的工作有望为理解如何提供分子框架。 生物活性脂质可微调血管和神经系统中的TRP通道功能。这些发现将反过来， 促进靶向TRP通道的策略的发展，而不破坏正常的生理学。