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.

我们当前的研究重点是研究生物活性脂质调节功能的机制 血管和感觉瞬态接收器电位（TRP）离子通道。 TRP离子频道的成员 亚科参与各种物理过程，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通道功能障碍基础 不同的病理生理状况，例如疼痛超敏反应，周围神经病（例如，在 糖尿病），炎症，高血压，神经系统疾病（例如小脑共济失调）和肾脏疾病。自从 TRP渠道在健康和疾病中起关键作用，激动者和对手有许多挑战 由于其副作用，必须在临床试验中克服。我们设想新的策略会微调TRP 频道功能，同时保持其身体角色，可能会规避不希望的副作用 药物。在过去的五年中，我们已经深入了解了这种机制 多不饱和脂肪酸（PUFAS），磷酸肌醇脂质和二酰基甘油调节TRPV4的功能， TRPV1和TRPC6。结合各种体外和体内方法，我们旨在描述 ω-3 PUFA提高TRPV4功能及其改善通道介导的潜力的机制 血管功能障碍。此外，我们将专注于确定TRPV1 C末端的结构基础 与质膜的域相互作用以及TRPC通道对生物活性脂质的固有灵敏度。 综上所述，我们提出的工作有望提供分子框架，以理解 生物活性脂质在血管和神经系统中微调TRP通道功能。这些发现将依次 促进制定针对TRP渠道的策略，而不会破坏正常的生理。