Transgenic Targeting of Vascular G Protein Signaling

血管 G 蛋白信号转导的转基因靶向

基本信息

  • 批准号:
    7851325
  • 负责人:
  • 金额:
    $ 38.63万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2004
  • 资助国家:
    美国
  • 起止时间:
    2004-01-19 至 2012-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): In an agonist-dependent manner, G protein-coupled receptor kinases (GRKs) phosphorylate 7 transmembrane spanning receptors (7TMRs) leading to classical homologous desensitization. There are 7 GRKs (GRK1-7) and they appear to have specific 7TMR substrates. GRK-phosphorylated 7TMRs are inhibited from association with their normal heterotrimeric G protein binding partner via arrestin binding. Importantly, it has recently been appreciated that although classical signaling might be desensitized and/or downregulated with phosphorylation, alternative signaling pathways may now be uncovered that are stimulated by receptor phosphorylation. For example, a large portion of GRK phosphorylation of either angiotensin II or vasopressin receptor is GRK2 mediated and leads to arrestin recruitment and internalization. However, it has recently been shown that arrestin-mediated ERK activation subsequent to either angiotensin II or vasopressin stimulation requires GRK5 phosphorylation. In addition, 21-adrenergic receptors (21ARs) generally do not couple to the adenylyl cyclase inhibitory heterotrimeric G protein, Gi, however, data in cultured cells indicate that phosphorylation of 21ARs by GRK5 can allow for Gi-coupling due to GRK5 actions causing a dissociation between the carboxyl-tail of 21ARs and PSD-95. Gs-Gi switching has also been shown for the 22AR when this receptor is phosphorylated by protein kinase A (PKA). In vascular smooth muscle (VSM), 2AR-Gi coupling would have profound physiological effects since Gs mediates vasodilation whereas Gi activation leads to vasoconstriction. Therefore, understanding changes in 7TMR signaling subsequent to phosphorylation is critical to gain a better insight into how signaling may change during disease states. In fact, Gi has been implicated in the development and progression of hypertension in animal models of the disease. In addition, GRK5 expression and activity is elevated in hypertension and we have found that VSM overexpression of GRK5 alone is sufficient to cause hypertension. Importantly, we have preliminary data to suggest that GRK5 can induce Gs to Gi switching of 21ARs in VSM and that this is likely at least one mechanism underlying hypertension when GRK5 levels are increased. Our Central Hypothesis is that "non-classical" 7TMR signaling as modified by GRK5 facilitates alternative signaling pathways such that Gi-mediated signaling becomes a critical component in the exacerbation of VSM vasoconstriction in the development and/or progression of hypertension. The Specific Aims addressing this hypothesis include: 1. To elucidate the role of G protein preference switching through increased GRK5 expression. 2. To delineate how the lack of GRK5 affects alternative signaling pathways and the development of high blood pressure (BP). 3. To determine the role of VSM Gi-mediated signaling in the establishment of BP under normal and pathophysiological settings. PUBLIC HEALTH RELEVANCE: There are changes in expression levels of numerous proteins during disease states such as hypertension. It is important to determine how these proteins, and particularly proteins with enzymatic activity such as GRK5, disrupt normal signaling patterns to develop strategies to more effectively treat and/or prevent cardiovascular disease. Data from these experiments should also increase our understanding of 21AR signaling in the setting of high blood pressure and help in the development of novel antihypertensive therapeutic strategies.
描述(由申请人提供):G蛋白偶联受体激酶(GRKs)以激动剂依赖性方式磷酸化7跨膜受体(7 TMR),导致经典同源脱敏。有7种GRK(GRK 1 -7),它们似乎具有特异性的7 TMR底物。GRK-磷酸化的7 TMR被抑制通过抑制蛋白结合与其正常异源三聚体G蛋白结合配偶体结合。重要的是,最近已经认识到,尽管经典信号转导可能被磷酸化脱敏和/或下调,但现在可以发现受受体磷酸化刺激的替代信号转导途径。例如,血管紧张素II或加压素受体的GRK磷酸化的大部分是GRK 2介导的,并导致抑制蛋白募集和内化。然而,最近的研究表明,血管紧张素II或加压素刺激后抑制素介导的ERK激活需要GRK 5磷酸化。此外,21-肾上腺素能受体(21 AR)通常不与腺苷酸环化酶抑制性异源三聚体G蛋白Gi偶联,然而,培养细胞中的数据表明,由于GRK 5作用导致21 AR的羧基尾与PSD-95之间的解离,GRK 5对21 AR的磷酸化可以允许Gi偶联。当22 AR受体被蛋白激酶A(PKA)磷酸化时,也已经显示了22 AR的Gs-Gi转换。在血管平滑肌(VSM)中,2AR-Gi偶联将具有深刻的生理效应,因为Gs介导血管舒张,而Gi活化导致血管收缩。因此,了解磷酸化后7 TMR信号的变化对于更好地了解疾病状态期间信号如何变化至关重要。事实上,Gi在高血压动物模型中与高血压的发展和进展有关。此外,GRK 5的表达和活性在高血压中升高,并且我们已经发现单独的GRK 5的VSM过表达足以引起高血压。重要的是,我们有初步的数据表明GRK 5可以诱导VSM中21 AR的Gs到Gi转换,并且当GRK 5水平增加时,这可能是高血压的至少一种潜在机制。我们的中心假设是,GRK 5修饰的“非经典”7 TMR信号转导促进替代信号转导途径,使得Gi介导的信号转导成为高血压发展和/或进展中VSM血管收缩恶化的关键组分。解决这一假设的具体目标包括:1。阐明通过增加GRK 5表达的G蛋白偏好转换的作用。2.阐明GRK 5的缺乏如何影响替代信号通路和高血压(BP)的发展。3.确定VSM Gi介导的信号传导在正常和病理生理环境下建立BP中的作用。公共卫生相关性:在疾病状态(如高血压)期间,许多蛋白质的表达水平会发生变化。重要的是要确定这些蛋白质,特别是具有酶活性的蛋白质,如GRK 5,如何破坏正常的信号传导模式,以制定更有效地治疗和/或预防心血管疾病的策略。这些实验的数据也应该增加我们对高血压背景下21 AR信号传导的理解,并有助于开发新的抗高血压治疗策略。

项目成果

期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Regulation of GPCR signaling in hypertension.
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KARSTEN PEPPEL其他文献

KARSTEN PEPPEL的其他文献

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{{ truncateString('KARSTEN PEPPEL', 18)}}的其他基金

S100A1: A Novel Modulator of Myocardial Infarct Inflammation and Regeneration
S100A1:心肌梗塞炎症和再生的新型调节剂
  • 批准号:
    7837490
  • 财政年份:
    2009
  • 资助金额:
    $ 38.63万
  • 项目类别:
S100A1: A Novel Modulator of Myocardial Infarct Inflammation and Regeneration
S100A1:心肌梗塞炎症和再生的新型调节剂
  • 批准号:
    8212057
  • 财政年份:
    2008
  • 资助金额:
    $ 38.63万
  • 项目类别:
Inflammation in Vein Graft Disease: A Genetic Approach
静脉移植疾病中的炎症:遗传方法
  • 批准号:
    6913614
  • 财政年份:
    2004
  • 资助金额:
    $ 38.63万
  • 项目类别:
Inflammation in Vein Graft Disease: A Genetic Approach
静脉移植疾病中的炎症:遗传方法
  • 批准号:
    7273694
  • 财政年份:
    2004
  • 资助金额:
    $ 38.63万
  • 项目类别:
Inflammation in Vein Graft Disease: A Genetic Approach
静脉移植疾病中的炎症:遗传方法
  • 批准号:
    7320959
  • 财政年份:
    2004
  • 资助金额:
    $ 38.63万
  • 项目类别:
Inflammation in Vein Graft Disease: A Genetic Approach
静脉移植疾病中的炎症:遗传方法
  • 批准号:
    6823419
  • 财政年份:
    2004
  • 资助金额:
    $ 38.63万
  • 项目类别:
Inflammation in Vein Graft Disease: A Genetic Approach
静脉移植疾病中的炎症:遗传方法
  • 批准号:
    7079259
  • 财政年份:
    2004
  • 资助金额:
    $ 38.63万
  • 项目类别:
TNF-INHIBITOR GENE THERAPY FOR NEOINTIMAL HYPERPLASIA
肿瘤坏死因子抑制剂基因治疗新生内膜增生
  • 批准号:
    6878609
  • 财政年份:
    2001
  • 资助金额:
    $ 38.63万
  • 项目类别:
TNF-INHIBITOR GENE THERAPY FOR NEOINTIMAL HYPERPLASIA
肿瘤坏死因子抑制剂基因治疗新生内膜增生
  • 批准号:
    6537782
  • 财政年份:
    2001
  • 资助金额:
    $ 38.63万
  • 项目类别:
TNF-INHIBITOR GENE THERAPY FOR NEOINTIMAL HYPERPLASIA
肿瘤坏死因子抑制剂基因治疗新生内膜增生
  • 批准号:
    6285923
  • 财政年份:
    2001
  • 资助金额:
    $ 38.63万
  • 项目类别:

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