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The functional characterization of two regulators of G-protein signaling proteins abundantly expressed in vascular smooth muscle cells.

机译：在血管平滑肌细胞中大量表达的G蛋白信号转导蛋白的两个调节剂的功能表征。

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摘要

Precise regulation of heterotrimeric G-protein signaling is important for maintaining proper cardiovascular system function. Indeed, G-protein signaling is frequently upregulated during cardiovascular disease suggesting that identifying mechanisms for inhibiting G-protein signaling may be an effective therapeutic strategy for the treatment and prevention of disease. The work presented in this thesis is directed at two RGS proteins, RGS2 and RGS5, the two highest expressing RGS proteins in VSMCs. Despite the large number of studies published on them, there is still much to be learned about the specific G-protein pathways that each RGS protein controls. Using genetic and molecular models, we set out to identify novel regulatory pathways controlling RGS2 and RGS5 function. We hypothesize that characterizing the determinants and regulation of RGS protein function will provide a better understanding of the signaling that occurs within VSMCs under both physiologic and pathophysiologic conditions.;Finally, our last study focuses on the function and regulation of RGS5, the single highest expressing RGS protein in VSMCs. We show that the regulation of RGS5 is dependent, similar to other VSMC-specific genes, on the activity of SRF and myocardin. However, interestingly, RGS5 expression is further controlled by the extent of DNA methylation that occurs in its proximal promoter. We show that this is an important regulator of RGS5 expression both in development as well as during disease, specifically in-stent restenosis.;Our work presented in the first three studies of this thesis, describes novel regulatory pathways that are involved in regulating RGS2 protein function. We describe the production of RGS2 protein isoforms that are the result of alternative translational start site usage. Interestingly, the expression pattern of these proteins is controlled by the signaling status of the cell. In the second two studies, we identify a functional consequence of RGS2-interaction with the plasma membrane. We show that this is dependent on the interaction between the amphipathic alpha-helix and anionic phospholipids present in the plasma membrane. We further show that disruptions in this interaction, as occurs in the human population, can lead to reduced RGS2 function and thus potentially hypertension.
机译：异源三聚体G蛋白信号的精确调节对于维持适当的心血管系统功能很重要。实际上，在心血管疾病期间，G蛋白信号传导经常被上调，这表明识别抑制G蛋白信号传导的机制可能是治疗和预防疾病的有效治疗策略。本文提出的工作针对两种RGS蛋白RGS2和RGS5，这两种蛋白在VSMC中表达最高。尽管已发表了大量研究，但每种RGS蛋白控制的特定G蛋白途径仍需学习很多。使用遗传和分子模型，我们着手确定控制RGS2和RGS5功能的新型调控途径。我们假设表征RGS蛋白功能的决定因素和调节将提供对生理和病理生理条件下VSMC中发生的信号转导的更好理解。;最后，我们的最后一项研究集中于RGS5的功能和调节，这是表达最高的单个VSMC中的RGS蛋白。我们显示，类似于其他VSMC特异性基因，RGS5的调控依赖于SRF和心肌素的活性。但是，有趣的是，RGS5的表达进一步受到其近端启动子中发生的DNA甲基化程度的控制。我们显示这是RGS5表达的重要调节剂，无论在发育中还是在疾病期间，尤其是支架内再狭窄。;我们在本文的前三项研究中介绍的工作描述了参与调节RGS2蛋白的新型调节途径功能。我们描述了RGS2蛋白同工型的产生，这些产物是替代翻译起始位点使用的结果。有趣的是，这些蛋白质的表达模式受细胞信号状态的控制。在后两个研究中，我们确定了RGS2与质膜相互作用的功能结果。我们表明这取决于两亲性α-螺旋和质膜中存在的阴离子磷脂之间的相互作用。我们进一步表明，这种相互作用的破坏（如在人群中发生）可能导致RGS2功能降低，从而可能导致高血压。

著录项

  • 作者

    Gu, Steven.;

  • 作者单位

    University of Toronto (Canada).;

  • 授予单位 University of Toronto (Canada).;
  • 学科 Biology Physiology.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 226 p.
  • 总页数 226
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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