REGULATION OF SERUM PROTEIN COMPOSITION IN NEPHROSIS

肾病血清蛋白组成的调节

• 批准号: 3243345
• 负责人: GEORGE ALAN KAYSEN
• 金额: $ 15.68万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-02-15 至 1994-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3243345
• 关键词: RNA; acute phase protein; alpha 1 acid glycoprotein; alpha 1 antitrypsin; deficient growth media; dietary proteins; electrophoresis; genetic strain; genetic transcription; glomerular filtration; hemoprotein biosynthesis; hemoprotein metabolism; hypoalbuminemia; laboratory rabbit; laboratory rat; liver cells; macroglobulins; molecular weight; nephrotic syndrome; nucleic acid hybridization; nucleic acid probes; nutrition related tag; proteinuria; radiotracer; sheep; tissue /cell culture; transferrin

The nephrotic syndrome is characterized by altered glomerular permselectivity causing the urinary loss of proteins of intermediate molecular weight (MW). Although albumin synthesis is increased by over 3 fold, its serum concentration decreases to less than 25% of normal, causing a fall in serum oncotic pressure (pl). In contrast to albumin, the serum concentration of many high MW proteins is increased in nephrosis, helping to defend pl, as well as in rats with hereditary analbuminemia (HA), animals with no significant urinary protein loss. Proteins in intermediate NW (transferrin, gamma globulin and a globulins) are also increased in HA rats, suggesting that reduced serum pl rather than either urinary protein loss or increased albumin synthesis is the stimulus for increased production of both intermediate and high MW proteins. We hypothesize that serum pl regulates the synthesis of a specific array of acute phase reactant proteins , and further that this control mechanism acts at the level of gene transcription. To test the hypothesis we will determine the relationship between pl and the rate of synthesis and catabolism of a group of acute phase reactant proteins of a range of MW's (alpha1AG, alpha1 antitrypsin, transferrin, alpha2 macroglobulin), and determine the hepatic steady state levels and rate of transcription of each species of mRNA in two experimental animal models: 1) Sprague Dawley rats (SD) with the nephrotic syndrome: a model of reduced pl caused by urinary protein loss, and 2) HA rats: a model of reduced pl with no external protein loss. We will further determine whether increasing serum pl to normal in nephrotic rats and rats with HA by the infusion of hetastarch or polyvinylpyrrolodone, suppresses increased synthesis of these proteins and of their mRNA's. Using cultured hepatocytes isolated from normal SD and HA rats, we will determine the relationship between pl and the synthesis of albumin, transferrin, a1AG, a1 antitrypsin, a2 macroglobulin and steady state concentration and rate of transcription of their mRNA's in response to varying concentrations of albumin, PVP and hetastarch in the culture medium. Since we have shown that dietary protein restriction prevents enhanced expression of the albumin gene when serum pl is reduced, we will also determine whether protein restriction modulates the response of other proteins to reduced serum pl. If these studies indicate that serum pl regulates the synthesis of an array of proteins at the level of gene transcription, we will initiate molecular studies to define the factor(s) which control this response.

肾病综合征的特征是肾小球改变。 渗透性选择性导致尿液中蛋白质的丢失 分子量(MW)。尽管白蛋白合成增加了3%以上 倍数，其血清浓度降至正常的25%以下，导致 血清肿胀压(Pl)下降。与白蛋白相比，血清 肾病时许多高分子量蛋白质的浓度增加，这有助于 为了保护pl，以及在遗传性蛋白血症(HA)大鼠中， 无明显尿蛋白丢失的动物。中间体中的蛋白质 NW(转铁蛋白、丙种球蛋白和α球蛋白)在HA中也增加 大鼠，这表明降低血清磷脂而不是尿蛋白 白蛋白合成的丧失或增加是增加的刺激因素 中高分子量蛋白质的生产。我们假设 血清磷脂酶调节一系列特定急性时相的合成 反应物蛋白质，而且这一控制机制作用于 基因转录水平。为了检验假设，我们将确定 磷脂酰胆碱与群体合成和分解代谢的关系 一系列分子量(α1AG，α1)的急性时相反应物蛋白 抗胰蛋白酶、转铁蛋白、α2巨球蛋白)，并测定肝脏 不同种类基因转录水平和转录速率的稳态变化 两种实验动物模型：1)SD大鼠(SD) 肾病综合征：一种尿蛋白丢失所致的PL降低模型， (2)HA大鼠：PL降低，无外源性蛋白丢失的模型。我们 将进一步确定肾病患者血清PL是否升高至正常 大鼠和HA大鼠输注羟乙基淀粉或 聚乙烯吡咯烷酮，抑制这些蛋白质的合成增加，并 从正常SD和HA分离的培养肝细胞 大鼠，我们将确定PL与合成的关系。 白蛋白、转铁蛋白、a1AG、a1抗胰蛋白酶、a2巨球蛋白和稳定 作为响应的它们的mRNA的状态浓度和转录速率 对不同浓度的白蛋白、PVP和赫赛汀的影响 5~6成熟。因为我们已经证明限制饮食蛋白质可以防止 白蛋白基因表达增强当血清pl降低时，我们将 也要确定蛋白质限制是否会调节其他 蛋白质，以降低血清pl。如果这些研究表明血清p1 在基因水平上调节一系列蛋白质的合成 转录，我们将启动分子研究来定义该因子(S) 它们控制着这种反应。