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鉴定和验证G蛋白结合受体调节血管内皮细胞的流量依赖信号通路

Dike Qiu¹, Ke Xu¹, Namjin Chung¹

¹Research and Early Development, Bristol Myers Squibb Company, Princeton, NJ, United States.

Frontiers in molecular biosciences

|June 26, 2023

概括

研究人员确定了G蛋白结合受体 (GPCRs),这些受体调节了内皮细胞中的克鲁佩尔样因子2 (KLF2) 表达. 这些GPCRs代表了心血管疾病的潜在治疗点.

科学领域:

心血管生物学心血管生物学
内皮细胞生物学内皮细胞生物学
分子医学是分子医学.

背景情况:

血管内皮细胞经历来自血液流动的机械力,影响心血管健康.
层状血流模式促进内皮细胞的健康,部分由克鲁佩尔样因子2 (KLF2) 转录因子介导.
识别KLF2的调节者对于开发新的心血管疾病疗法至关重要.

研究的目的:

发现KLF2转录程序的新型内皮细胞调节剂.
为了确定调节KLF2表达的G蛋白结合受体 (GPCRs).
探索心血管疾病的潜在治疗点.

主要方法:

生物信息分析与使用小干扰RNA (siRNAs) 的向基因淘汰相结合.
对内皮细胞GPCRs进行基因查,以确定它们对KLF2表达的影响.
在初级内皮细胞中确定GPCRs (GPR116,SSTR3,GPR101,LGR4) 的验证.

主要成果:

确定了12个潜在的GPCR目标,调节KLF2程序.
一组GPCRs的子集证明了对流动诱导的KLF2表达的调节.
特定的GPCRs (GPR116,SSTR3,GPR101,LGR4) 已被证明会影响KLF2的转录激活.
启动了LGR4的药物发现,确定了第一个合成配体.

结论:

内皮GPCRs是KLF2通路的关键调节者.
已识别的GPCRs (GPR116,SSTR3,GPR101,LGR4) 是心血管疾病的潜在治疗标.
针对LGR4的药物发现工作显示出途径导向疗法的前景.

关键词:

G蛋白结合受体的受体是什么在 GPR101 中,GPR101 是一个简单的语法.在KLF2KLF2KLF2 在LGR4LGR4LGR4 这是一种β-arrestin.发现药物的发现.它们是内皮细胞的内皮细胞.层状流的流量层状流

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G-protein Coupled Receptors

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