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Brain ischemia attenuates neuropeptide biosynthesis

脑缺血减弱神经肽生物合成

基本信息

批准号：
7341704
负责人：
AN ZHOU
金额：
$ 30.59万
依托单位：
LEGACY EMANUEL HOSPITAL AND HEALTH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-12-15 至 2009-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7341704
关键词：
Adverse effects Affect Anabolism Animals Apoptotic Attenuated Biochemical Biological Process Brain Brain Injuries Brain Ischemia Calcium Cell Death Cells Cellular biology Condition Cultured Cells Data Defect Development Disease Enzymes Exhibits Genes Glucose Goals In Vitro Injury Ischemia Ischemic Brain Injury Ischemic Stroke Knockout Mice Mediating Modeling Molecular Molecular Biology Neurons Neuropeptides Neurosecretory Systems Oxygen Pathway interactions Peptides Play Principal Investigator Process Production Proprotein Convertase 1 Proprotein Convertase 2 Protein Analysis Proteins Proteomics Rattus Research Role Simulate Stress Stroke System Testing Therapeutic Intervention Transcript Wild Type Mouse Work attenuation biological adaptation to stress brain cell carboxypeptidase H deprivation functional status neglect neuron loss novel peptide hormone programs response

项目摘要

DESCRIPTION (provided by applicant): Neuropeptides play crucial roles in maintaining normal function of the brain and the brain's response to stresses, e.g. ischemia. Virtually all known neuropeptides are processed from larger precursors by the action of a set of processing enzymes in the secretory pathway. The biological function of precursor forms may differ profoundly from that of final processed forms to include even a switch from pro-apoptotic rather than anti-apoptotic function. Little is known about how the biosynthetic processing of neuropeptides may be affected by ischemic stress in the brain. Our preliminary studies indicate that ischemia causes attenuation in the activation of key neuropeptide processing enzymes and an accumulation of certain neuropeptides in precursor forms. Our hypothesis is: ischemia has adverse effects on the functional status of the neuropeptide processing system, thus impairing the ability of brain cells to produce certain protective peptide factors. This ischemia-induced attenuation of neuropeptide processing contributes to post-ischemia cell death in the brain. In the proposed study, we will first examine changes in the expression levels of several key neuropeptide processing enzymes and their enzymatic activities in ischemic rat brains. Then, we will determine the levels and molecular forms of neuropeptides that are known to have modulatory roles in the brain after ischemia and to require the action of processing enzymes investigated in this study for proper processing. Using in vitro ischemia models in cultured cells, we will investigate how ischemic stress may influence the activation and maturation processes of the processing enzymes and alter the production and secretion of neuropeptides. In parallel, we will analyze peptides secreted from ischemic cells using a quantitative proteomic approach. Finally, we will investigate if animals with specific deficiencies in neuropeptide processing may be more vulnerable to ischemic stress and determine if peptides secreted from processing-deficient neuronal cells may cause or exaggerate ischemic cells death. The proposed study will offer a novel mechanism concerning how ischemic stroke may damage the brain by attenuating neuropeptide processing. Our long-term goal is to elucidate the molecular mechanisms of neuropeptide processing-mediated stress response of the brain.

描述（由申请人提供）：神经肽在维持大脑正常功能和大脑对应激（如缺血）的反应中起着至关重要的作用。几乎所有已知的神经肽都是通过分泌途径中一系列加工酶的作用从较大的前体加工而成的。前体形式的生物学功能可能与最终加工形式有很大不同，甚至包括从促凋亡而不是抗凋亡功能的转换。关于神经肽的生物合成过程如何受到脑缺血应激的影响，我们所知甚少。我们的初步研究表明，缺血导致关键神经肽加工酶的激活减弱和某些前体形式神经肽的积累。我们的假设是：缺血对神经肽加工系统的功能状态产生不利影响，从而损害脑细胞产生某些保护性肽因子的能力。这种缺血诱导的神经肽加工衰减有助于脑缺血后细胞死亡。在本研究中，我们将首先研究缺血大鼠脑中几种关键神经肽加工酶的表达水平及其酶活性的变化。然后，我们将确定已知在缺血后大脑中具有调节作用的神经肽的水平和分子形式，并需要本研究中研究的加工酶的作用来进行适当的加工。利用体外培养细胞缺血模型，我们将研究缺血应激如何影响加工酶的激活和成熟过程，并改变神经肽的产生和分泌。同时，我们将使用定量蛋白质组学方法分析从缺血细胞分泌的肽。最后，我们将研究神经肽加工特异性缺陷的动物是否更容易受到缺血应激的影响，并确定加工缺陷神经元细胞分泌的肽是否会导致或加剧缺血细胞的死亡。提出的研究将提供一个关于缺血性中风如何通过减弱神经肽加工损害大脑的新机制。我们的长期目标是阐明神经肽加工介导的大脑应激反应的分子机制。