Regulation of guanylyl cyclase

鸟苷酸环化酶的调节

• 批准号: 7118893
• 负责人: FERID MURAD
• 金额: $ 10.4万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7118893
• 关键词: apoptosis; biological signal transduction; cell differentiation; cyclic GMP; cytotoxicity; enzyme activity; enzyme linked immunosorbent assay; enzyme mechanism; gel mobility shift assay; genetic transcription; guanylate cyclase; intracellular; messenger RNA; neuroblastoma; nitric oxide; oxidative stress; polymerase chain reaction; second messengers; site directed mutagenesis; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant): Soluble guanylyl cyclase (sGC) is one of the crucial enzymes in the NO-cyclic GMP (cGMP) signaling cascade involved in smooth muscle relaxation, inhibition of platelet aggregation, and neurotransmission. sGC is the target of various pharmacological compounds currently used for treatment of cardiovascular disorders. However, the mechanisms governing stimulation of activity or expression of sGC are poorly understood. Effective manipulation of sGC-dependent synthesis of cGMP for therapeutic purposes requires understanding of the pathways involved in regulation of sGC levels and activity. The goal of this proposal is to determine the molecular mechanism of enzyme activation by alisoteric effectors including development of approaches for NO-independent regulation of sGC, investigation of the mechanisms regulating sGC expression, and analysis of the effects of short-term and long-term modulation of sGC activity and expression on cell physiology. To achieve this goal, a constitutively activated sGC mutant will be expressed in a cell model providing for elevated levels of cGMP, whereas expression of domains involved in formation of functional heterodimers of sGC will result in decreased enzyme levels and lowered NO-dependent synthesis of cGMP. The promoter fragments of sGC genes will be identified and characterized as well as the mechanisms of post-transcriptional regulation of sGC Human cell culture models will be developed and the effects of short-term and long-term sGC regulation on cell physiology will be determined. The knowledge of the mechanism of sGC regulation will advance our understanding of the role of sGC/cGMP system in various biological processes.

描述（由申请人提供）：可溶性圭尼环酶（SGC）是无周期性GMP（CGMP）信号级联中的关键酶之一，涉及平滑肌松弛，抑制血小板聚集的抑制，以及神经传递。 SGC是目前用于治疗心血管疾病的各种药理化合物的靶标。但是，对刺激活性或SGC表达的机制知之甚少。有效地操纵SGC依赖性CGMP用于治疗目的的合成需要了解SGC水平和活性调节所涉及的途径。该提案的目的是确定通过情感效应子来确定酶激活的分子机制，包括开发无独立调节SGC的方法，调查调节SGC表达的机制以及对SGC活性和对细胞生理学的短期和长期调节的影响的分析。为了实现这一目标，组成型激活的SGC突变体将在细胞模型中表达，以升高CGMP水平，而与SGC的功能异二聚体形成有关的域的表达将导致酶水平降低并降低CGMP的无依赖性合成。将确定并表征SGC基因的启动子片段，以及SGC人类细胞培养模型的转录后调节机制，并确定短期和长期SGC调节对细胞生理的影响。对SGC调节机制的了解将提高我们对SGC/CGMP系统在各种生物过程中的作用的理解。

项目成果

Mapping sites of tyrosine nitration by matrix-assisted laser desorption/ionization mass spectrometry.

通过基质辅助激光解吸/电离质谱法绘制酪氨酸硝化位点。

• DOI: 10.1016/s0076-6879(05)96023-0
• 发表时间: 2005
• 期刊: Methods in enzymology.
• 作者: Turko,IllarionV;Murad,Ferid
• 通讯作者: Murad,Ferid

Effects of nitric oxide on skin burn wound healing.

一氧化氮对皮肤烧伤伤口愈合的影响。

• DOI: 10.1097/bcr.0b013e3181848119
• 发表时间: 2008
• 期刊: Journal of burn care & research : official publication of the American Burn Association
• 作者: Zhu,Haifeng;Wei,Xiaofei;Bian,Ka;Murad,Ferid
• 通讯作者: Murad,Ferid