TRANSGENIC STUDY VASCULAR ROLE OF NEUROPEPTIDE Y

神经肽 Y 的转基因研究血管作用

• 批准号: 6439161
• 负责人: Mieczyslaw Michael MICHALKIEWICZ
• 金额: $ 13.24万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-15 至 2002-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6439161
• 关键词: blood pressure; genetically modified animals; hypertension; laboratory rat; neuropeptide Y; neuropeptide receptor; norepinephrine; protein localization; receptor expression; vascular resistance; vascular smooth muscle nervous control; vasomotion

Neuropeptide Y (NPY) with its multiple receptor subtypes is emerging as an important sympathetic regulator of cardiovascular and metabolic functions. Very potent vasoconstrictor and appetite stimulating activities of NPY suggest the physiological importance of this peptide and its involvement in the pathogenesis of hypertension and obesity. Antagonizing specific NPY activities may offer new avenues for treatment these diseases. This project tests the hypothesis that endogenous NPY by activating its own receptor increases vascular tone directly or indirectly by modulating adrenergic transmission to the blood vessels and that an increased chronic expression of the NPY gene will cause the development of hypertension. To test this hypothesis the NPY transgenic of Sprague Dawley rats were generated in which endogenous NPY is overexpressed under its natural promoter allowing for physiological regulation in the constitutive sites. These animals develop persistent hypertension with mildly elevated body weight. Using this model, the role of NPY and its newly discovered receptors in the long-term regulation of cardiovascular functions will be determined. Four Specific Aims are proposed: (1) Analyze the pattern of NPY overexpression at the protein and mRNA levels in the NPY transgenic male and female rats with particular emphasis on the constitutive sites of endogenous NPY production involved in the cardiovascular regulation; (2a) Determine the effect of NPY overexpression on arterial blood pressure and vascular resistance in male and female rats; and (2b) using available specific NPY receptor antagonists, identify the NPY receptor(s) involved in the development of the hypertension in the NPY transgenic rats; (3) Determine the effect of NPY overexpression on the adrenergic transmission to blood vessels by measuring a) pressor responsiveness to an adrenergic agonist norepinephrine (alpha1/alpha2); and b) (alpha1/ alpha2) responsiveness of the submandibular gland blood flow to supramaximal nerve stimulation; (4) Evaluate the contribution of increased food consumption and body weight to the development of the hypertension in the NPY transgenic rats using a pair feeding approach. This studies will determine the role of endogenous NPY and its receptors in a long-term regulation of blood pressure and the mechanisms of the cooperation between the sympathetic neurotransmitters. The NPY overexpressing rats with well defined mutation of the NPY gene will provide a new transgenic animal model of hypertension; such a model should also be very useful for development of new therapies for treating this diseases.

具有多个受体亚型的神经肽Y（NPY）正在出现 心血管和代谢的重要同情调节剂 功能。 非常有效的血管收缩和食欲刺激 NPY的活动表明该肽的生理重要性 及其参与高血压和肥胖症的发病机理。 对抗特定的NPY活动可能会提供新的治疗途径 这些疾病。 该项目检验了内源性NPY的假设 通过激活自己的受体直接增加血管张力或 间接通过调节肾上腺素能传播到血管 并且NPY基因的慢性表达增加将导致 高血压的发展。 为了检验该假设NPY转基因 生成了Sprague Dawley大鼠的内源性NPY是 在其天然启动子下过表达，可以生理 本构地点的调节。 这些动物持续发展 高血压，体重轻度升高。 使用此模型， NPY及其新发现的受体长期的作用 将确定心血管功能的调节。四个特定 提出了目的：（1）分析NPY过表达的模式 NPY转基因男性和雌性大鼠的蛋白质和mRNA水平 特别强调内源性NPY的组成部位 涉及心血管调节的生产； （2a）确定 NPY过表达对动脉血压和血管的影响 雄性和雌性大鼠的抗性； （2b）使用可用的特定 NPY受体拮抗剂，确定涉及的NPY受体 NPY转基因大鼠的高血压发育； （3） 确定NPY过表达对肾上腺素能的影响 通过测量a）向血管传输到血管 肾上腺素激动剂去甲肾上腺素（alpha1/alpha2）；和b）（alpha1/ alpha2）下颌腺体血流的反应性 神经超刺激； （4）评估 增加食物消耗和体重来发展 NPY转基因大鼠的高血压使用一对喂养方法。 这项研究将确定内源性NPY及其受体的作用 长期调节血压和机制 交感神经递质之间的合作。 npy 过表达NPY基因突变明确的大鼠将 提供一种新型的高血压转基因动物模型；这样的模型 对于开发用于治疗的新疗法也应该非常有用 这是疾病。