Aldosterone, G6PD, and Vascular Endothelial Function

醛固酮、G6PD 和血管内皮功能

基本信息

批准号：
7468068
负责人：
Jane A Leopold
金额：
$ 10.04万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-15 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7468068
关键词：
Address Adverse effects Aldosterone Award Basic Science Bioavailable Biology Blood Vessels Boston Cardiovascular system Cell physiology Cells Commit Condition Congestive Heart Failure Endothelial Cells Endothelium Environment Enzymes Functional disorder Gene Transfer Techniques Genetic Transcription Glucosephosphate Dehydrogenase Hypertension In Vitro Independent Scientist Award Institutes Investigation Mediating Modeling Molecular Mus NADP Nitric Oxide Oxidants Oxidation-Reduction Patients Pentosephosphate Pathway Physiological Post-Translational Protein Processing Principal Investigator Production Proteins Rate Renin-Angiotensin-Aldosterone System Research Signal Pathway Sodium Source Steroids Stress Transgenic Mice Transgenic Organisms Translations Universities Vascular Endothelial Cell Vasodilation career hybrid gene in vivo medical schools novel pressure prevent response time use

项目摘要

Elevated levels of aldosterone are associated with impaired endothelium-dependent vasodilation in patients with hypertension and congestive heart failure. Although poorly understood, several mechanisms have been implicated to explain the adverse effects of aldosterone on endothelial cell (EEC) function including decreased nitric oxide (NO.) production and/or increased oxidant stress (OS). The applicant has previously demonstrated that glucose-6- phosphate dehydrogenase (G6PD), the first enzyme in the pentose phosphate pathway and principal intracellular source of NADPH, modulates EC function by regulating nitric oxide (NO.) production and limiting vascular OS. Aldosterone-mediated inhibition of G6PD represents a unifying mechanism by which aldosterone may impair EC function and vasodilation. Aldosterone is known to influence gene transcription and inhibition of G6PD, in turn, will result in decreased NO. levels and increased vascular OS to promote EC dysfunction. With the Independent Scientist Award (K02), the applicant will use the time protected by this award examine the molecular mechanisms by which aldosterone modulates G6PD to impair EC function. The applicant will place an intensive research focus on studies that will examine the effect of aldosterone on G6PD expression and the resulting functional consequences in EC in vitro. The in vivo significance of these findings will be confirmed using novel vascular gene transfer techniques and transgenic murine models. The applicant is a principal investigator in the Whitaker Cardiovascular Institute at Boston University School of Medicine, which provides a rich intellectual environment to establish the groundwork for this line of investigation. As evidenced by seven years of vascular biology research, the applicant remains firmly committed to a long-term career in basic science investigation.

醛固酮水平升高与高血压和充血性心力衰竭患者的内皮血管舒张受损有关。尽管知之甚少，但已经牵涉到几种机制来解释醛固酮对内皮细胞功能（EEC）功能的不利影响，包括降低一氧化氮（NO。）产生和/或增加氧化剂应激（OS）。申请人先前已经证明，葡萄糖-6-磷酸脱氢酶（G6PD）是五磷酸五磷酸途径中的第一种酶和NADPH的主要细胞内来源，通过调节一氧化氮（no。）生产和限制血管OS来调节EC的功能。醛固酮介导的G6PD抑制作用代表了醛固酮可能损害EC功能和血管舒张的统一机制。已知醛固酮会影响基因转录和G6PD的抑制作用，反过来将导致NO降低。水平和增加的血管OS以促进EC功能障碍。在独立科学家奖（K02）的情况下，申请人将使用该奖项保护的时间检查醛固酮调节G6PD以损害EC功能的分子机制。申请人将重点研究研究，以研究醛固酮对醛固酮的影响 G6PD表达和EC体外的功能后果。这些发现的体内意义将使用新型的血管基因转移技术和转基因鼠模型确认。申请人是波士顿大学医学院惠特克心血管研究所的首席研究员，该学院提供了丰富的智力环境，为这一调查建立了基础。正如七年的血管生物学研究所证明的那样，申请人仍然坚定地致力于基础科学研究的长期职业。