MIF: A novel CNS regulator of cardiovascular function

MIF：心血管功能的新型中枢神经系统调节剂

• 批准号: 7239526
• 负责人: COLIN SUMNERS
• 金额: $ 49.65万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7239526
• 关键词: Acute; Affect; Angiotensin II; Binding; Blood Pressure; Brain; Brain Stem; Calcium; Calmodulin; Cardiovascular Physiology; Cardiovascular system; Cell Nucleus; Chronic; Depressed mood; Feedback; Fire - disasters; Gene Transfer; Goals; Hyperactive behavior; Hypertension; Hypothalamic structure; Immigration; In Vitro; Mediating; Membrane; Mental Depression; Migration Inhibitory Factor; Molecular; Neurons; Organ; Oxidases; Oxidoreductase; Peptides; Phosphotransferases; Physiological; Play; Production; Property; Protein Kinase C Alpha; Proteins; Publishing; Rattus; Reactive Oxygen Species; Receptor, Angiotensin, Type 1; Research Personnel; Role; Signaling Molecule; Sulfhydryl Compounds; Testing; base; calmodulin-dependent protein kinase II; chronotropic; depressive symptoms; factor A; in vivo; inhibitor/antagonist; neuronal circuitry; normotensive; novel; paraventricular nucleus; phenylpyruvate tautomerase; pressure; prevent; programs; receptor; response

DESCRIPTION (provided by applicant): Angiotensin II (Ang II) acts via neuronal Ang II type 1 receptors (AT1-R) within the brain to increase sympathetic outflow and blood pressure, and hyperactivity of these effects plays a major role in hypertension. Thus, factors that regulate the neuronal actions of Ang II in the brain will modify the effects of this peptide on blood pressure. The current proposal focuses on the role of macrophage migration inhibitory factor (MIF) as a possible intracellular regulator of these neuronal actions of Ang II, in particular at the paraventricular nucleus (PVN), a center for control of sympathetic outflow and blood pressure. Based on preliminary findings we have developed the novel hypothesis that MIF, produced within neurons in response to Ang II, acts as a chronic intracellular negative feedback regulator of Ang II's chronotropic actions. Specifically, the proposal is that: (i) In normotensive rat neurons MIF, produced in response to Ang II, exerts an inhibitory influence which dampens or prevents further stimulatory actions of Ang II on neuronal firing; (ii) MIF inhibits the neuronal chronotropic action of Ang II via it's thiol-oxidoreductase activity, scavenging of reactive oxygen species (ROS) and modulation of membrane K+ and Ca2+ currents; (iii) In normotensive rat PVN, Ang ll-induced increases in MIF expression serve to blunt or depress subsequent increases in sympathetic outflow and blood pressure elicited by Ang II. In this proposal our overall goal is to investigate a novel role of MIF as an inhibitor of Ang ll-induced responses in neurons. The above hypotheses will be tested through in vitro and in vivo studies that will combine cellular, molecular, gene transfer and physiological approaches. The specific aims are: (1) Investigate the role of MIF as an inhibitor of the chronotropic action of Ang II in neurons; (2) Investigate the intracellular mechanisms by which MIF affects the neuronal chronotropic actions of Ang II; (3) Determine the consequences of increased MIF expression in the PVN to Ang ll-induced cardiovascular effects. These studies will establish a role for MIF as an inhibitory regulator of the CNS actions of Ang II on sympathetic outflow and blood pressure, and will lay the groundwork for determining whether a lack of this MIF regulatory mechanism contributes to hypertension.

描述（由申请人提供）：血管紧张素II（ANG II）通过大脑内的神经元II受体（AT1-R）起作用，以增加交感神经流出和血压，并且这些作用的过度活跃在高血压中起主要作用。因此，调节ANG II在大脑中神经元作用的因素将改变该肽对血压的影响。当前的提案着重于巨噬细胞迁移抑制因子（MIF）作为ANG II神经元作用的可能细胞内调节剂，特别是在旁脑室核（PVN），这是交感神经外流和血压的控制中心。基于初步发现，我们开发了一种新的假设，即响应ANG II中在神经元内产生的MIF充当了ANG II的Chronotropic作用的慢性细胞内负反馈调节剂。具体而言，建议是：（i）在响应ANG II产生的正常大鼠神经元中发挥了抑制作用，从而抑制或阻止ANG II对神经元射击的进一步刺激作用； （ii）MIF通过其硫醇 - 氧化还原酶活性，清除活性氧（ROS）（ROS）和膜K+和Ca2+电流的调节来抑制ANG II的神经元表现作用； （iii）在正常的大鼠PVN中，ANG LL诱导的MIF表达的增加可钝化或降低随后的交感神经流出和ANG II引起的血压的增加。在此提案中，我们的总体目标是研究MIF作为ANG LL诱导的神经元反应的抑制剂的新作用。上述假设将通过体外和体内研究进行测试，该研究将结合细胞，分子，基因转移和生理方法。具体目的是：（1）研究MIF作为ANG II在神经元中的年代作用的抑制剂的作用； （2）研究MIF影响ANG II的神经元表现作用的细胞内机制； （3）确定PVN中MIF表达增加对ANG LL诱导的心血管效应的后果。这些研究将确立MIF作为ANG II对交感神经流出和血压的CNS作用的抑制性调节剂的作用，并将为确定缺乏这种MIF调节机制是否有助于高血压奠定基础。