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HEPATIC COMA--GLIAL BENZODIAZEPINE RECEPTORS & STEROIDS

肝昏迷--神经胶质苯二氮卓受体

基本信息

批准号：
6187284
负责人：
MICHAEL David NORENBERG
金额：
$ 16.32万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-08-15 至 2002-07-31
项目状态：
已结题

项目摘要

DESCRIPTION (Adapted from Applicant's Abstract): The investigator proposes, in this revised competitive renewal, to study the pathogenic mechanisms of hepatic encephalopathy. The mechanism which lead to hepatic encephalopathy are not well understood but in recent years there has been substantial evidence which implicates ammonia, astrocytes, and excessive GABAergic activity mediated by elevated levels of endogenous benzodiazepines. During the prior funding period, the investigator studied the role of astrocytes, ammonia and benzodiazepines in hepatic encephalopathy and in their prior studies they found that 1) ammonia upregulates the peripheral benzodiazepine receptor in cultured astrocytes an in animal models of hepatic encephalopathy and 2) peripheral benzodiazepine receptor (PBR) blockers ameliorate ammonia toxicity in vivo. They also found that neurosteroids (which are products of PBR activation) are elevated in animal models of hepatic encephalopathy and in ammonia treated astrocyte cultures, and that some of these neurosteroids exert behavioral and neuropathologic changes similar to hepatic encephalopathy. Their hypothesis is that neurosteroids that positively modulate the GABAA receptor contribute to the pathogenesis of HE. They further propose that the elevation of neurosteroids result from an upregulation of astrocytic PBR by the hyperammonemia associated with liver failure. To test the hypothesis, they plan to investigate the profile of neurosteroids in animal models of HE and ammonia treated astrocyte cultures. They plan to determine whether neurosteroids are elevated in HE and are able to reproduce the clinical, pathological, and neurochemical features of HE. They will also examine whether inhibiting the synthesis or action of neurosteroids that have a positive modulatory effect on the GABAA receptor will improve the outcome of the experimental HE. They plan to study the role of astrocytic PBRs in the generation of neurosteroids from brains of animal models of HE by investigating PBR binding parameters. Measuring PBR mRNA steady-state levels, and localizing changes in the PBR by in situ hybridization. The functional integrity of the PBR will be examined by measuring the rate of pregnenolone synthesis. To establish the role of ammonia in the PBR-dependent production of neurosteroids by astrocytes, similar studies will be carried out in cultured astrocytes. Their proposed mechanism, whereby ammonia upregulates the astrocytic PBR resulting in elevated levels of neurosteroids that act on the neuronal GABAA receptor synthesizes current pathogenic views and more importantly, provides the potential for novel therapeutic approaches through intervention of neurosteroid effects.

描述（改编自申请人摘要）：研究者提出，在这个修订的竞争性更新，研究致病机制，肝性脑病肝性脑病的发病机制并没有得到很好的理解，但近年来，有证据表明氨星形胶质细胞和过量的GABA能内源性苯二氮卓类药物水平升高介导的活性。期间在之前的资助期间，研究人员研究了星形胶质细胞的作用，氨和苯二氮卓类药物在肝性脑病中的作用，研究发现，1）氨上调外周苯二氮卓类受体在培养的星形胶质细胞和动物模型的肝脑病和2）外周苯二氮卓受体（PBR）阻滞剂改善体内氨毒性。他们还发现神经类固醇（其是PBR活化的产物）在以下动物模型中升高：肝性脑病和氨处理的星形胶质细胞培养物，这些神经类固醇中的一些产生行为和神经病理学变化类似于肝性脑病他们的假设是神经类固醇积极调节GABAA受体有助于发病机制他的。他们进一步提出，神经类固醇的升高是由于高氨血症导致星形胶质细胞PBR上调，肝衰竭为了验证这一假设，他们计划调查 HE和氨水处理的星形胶质细胞动物模型中神经甾体的含量 cultures. 他们计划确定HE中神经类固醇是否升高并且能够重现临床病理和神经化学他的特点。他们还将研究是否抑制合成或神经类固醇的作用对GABAA具有积极的调节作用受体将改善实验性HE的结果。他们计划研究星形胶质细胞PBRs在神经甾体生成中的作用， HE动物模型脑组织PBR结合参数的测定。测量PBR mRNA稳态水平，并通过以下方法定位PBR的变化：原位杂交将检查PBR的功能完整性通过测量双烯醇酮的合成速率。确立…的作用氨在星形胶质细胞的神经类固醇的PBS依赖性生产中，将在培养的星形胶质细胞中进行类似的研究。他们提出的机制，从而氨上调星形胶质细胞PBR，作用于神经元GABAA受体的神经类固醇水平升高综合了当前的致病观点，更重要的是，潜在的新的治疗方法，通过干预神经类固醇效应