Regulation of BileAcid Synthesis by a alpha1-AT Peptide
Regulation of BileAcid Synthesis by a alpha1-AT Peptide
批准号:
6676635
负责人:
GREGORIO GIL
金额:
$36.61万
依托单位国家:
美国
项目类别:
财政年份:
2003
资助国家:
美国
项目状态:
已结题
起止时间:
2003-09-01 至 2008-06-30
关键词:
alpha 1 antitrypsin alpha fetoprotein cholanate compound enzyme activity genetic regulation genetic transcription hamsters homeostasis inflammation intermolecular interaction laboratory mouse steroid 7alpha hydroxylase steroid biosynthesis steroid metabolism tissue /cell culture transcription factor
中文摘要
描述(由申请人提供):胆汁酸合成在维持胆固醇稳态中起着至关重要的作用,因为它负责从体内排出的50%以上的胆固醇的分解代谢。高血浆胆固醇常导致动脉粥样硬化,这是一种慢性炎症。在炎症反应中,α 1-抗胰蛋白酶(α 1 -AT)的合成速率增加。α 1-抗胰蛋白酶是一种血清蛋白酶抑制剂,在肝脏中合成,其合成速率在炎症反应中增加。α - 1- at合成的增加引起肽的增加,如其羧基端C-36肽,这是由蛋白酶裂解α - 1- at引起的。由于血浆胆固醇水平、炎症和α - 1- at合成速率之间存在相关性,我们研究了C-36蛇形肽对肝脏胆汁酸生物合成的影响,发现C-36是一种强大的特异性转录下调因子,通过抑制胆固醇7 α -羟化酶/CYP7A1 (7 α -羟化酶)和甾醇12 α -羟化酶/CYP8B1 (12 α -羟化酶)启动子来下调胆汁酸合成。这种抑制似乎是通过与α 1-胎蛋白转录因子(FTF)特异性相互作用介导的,FTF是胆汁酸生物合成的一个关键阳性转录因子。我们假设C-36肽特异性地与FTF相互作用,这种相互作用抑制了7 α -和12 α -羟化酶启动子的活性。我们提出实验来验证这一假设,并研究FTF蛋白和α 1- at衍生的C-36肽这两个分子之间相互作用的分子机制。本建议的具体目的是:1。测定a1-AT衍生的C-36肽对动物胆汁酸生物合成的影响。2. 测定α 1- at衍生的C-36肽在培养细胞和动物中的亚细胞靶向性。3. α 1- at衍生的C-36肽调控7α -和12α -羟化酶基因转录的作用机制。4. α - 1- at启动子的表征及其C-36肽的自我调节。该项目的成功完成可能为胆固醇稳态和炎症之间提供了重要的联系。
英文摘要
DESCRIPTION (provided by applicant): Bile acid synthesis plays a crucial role in maintaining cholesterol homeostasis since it is responsible for the catabolism of more than 50% of the cholesterol excreted from the body. High plasma cholesterol often results in atherosclerosis, which is a form of chronic inflammation. In response to inflammation, the rate of synthesis of alpha1-antitrypsin (alpha1 -AT) increases. Alpha1-antitrypsin is a serum protease inhibitor that is synthesized in the liver and its rate of synthesis increases in response to inflammation. This increase in alpha1-AT synthesis gives rise to an increase in peptides, like its carboxy-terminal C-36 peptide, resulting from alpha1-AT cleavage by proteases. Because of this correlation between plasma cholesterol levels, inflammation and alpha1-AT rate of synthesis, we investigated the effect of the C-36 serpin peptide on hepatic bile acid biosynthesis and showed that C-36 is a powerful and specific transcriptional down-regulator of bile acid synthesis through inhibition of the cholesterol 7alpha-hydroxylase/CYP7A1 (7alpha-hydroxylase) and sterol12alpha-hydroxylase/CYP8B1 (12alpha-hydroxylase) promoters. This inhibition appears to be mediated by specifically interacting with alpha1-fetoprotein transcriptional factor (FTF), a positive transcriptional factor key in bile acid biosynthesis. We hypothesize that the C-36 peptide specifically interacts with FTF, and this interaction suppresses 7alpha- and 12alpha-hydroxylase promoter activities. Experiments are proposed to validate this hypothesis and to study the molecular mechanisms involved in the interaction between these two molecules, the FTF protein and the alpha1-AT-derived C-36 peptide. The specific aims of this proposal are: 1. Determine the effect of the a1-AT derived C-36 peptide on bile acid biosynthesis in animals. 2. Determine the subcellular targeting of the alpha1-AT derived C-36 peptide in both culture cells and animals. 3. Characterization of the mechanism of action involved in the regulation of 7alpha- and 12alpha-hydroxylase gene transcription by the alpha1-AT derived C-36 peptide. 4. Characterization of the alpha1-AT promoter and its self-regulation by the C-36 peptide. The successful completion of this project may provide an important link between cholesterol homeostasis and inflammation.
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会议论文
Role of Star Proteins in Bile Acid and Cholesterol Metabolism
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批准号:8096701
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项目类别:
-
资助金额:$31.87万
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财政年份:2009
-
负责人:GREGORIO GIL
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依托单位:
Regulation of Bile Acid Synthesis by Nuclear Receptors in Vivo
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批准号:7579713
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项目类别:
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资助金额:$35.82万
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财政年份:2009
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负责人:GREGORIO GIL
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依托单位:
Role of Star Proteins in Bile Acid and Cholesterol Metabolism
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批准号:8282879
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项目类别:
-
资助金额:$31.87万
-
财政年份:2009
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负责人:GREGORIO GIL
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依托单位:
Regulation of Bile Acid Synthesis by Nuclear Receptors in Vivo
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批准号:7752527
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项目类别:
-
资助金额:$35.52万
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财政年份:2009
-
负责人:GREGORIO GIL
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依托单位:
Regulation of Bile Acid Synthesis by Nuclear Receptors in Vivo
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批准号:8207967
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项目类别:
-
资助金额:$31.87万
-
财政年份:2009
-
负责人:GREGORIO GIL
-
依托单位:
Role of Star Proteins in Bile Acid and Cholesterol Metabolism
-
批准号:7866643
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项目类别:
-
资助金额:$35.52万
-
财政年份:2009
-
负责人:GREGORIO GIL
-
依托单位:
Role of Star Proteins in Bile Acid and Cholesterol Metabolism
-
批准号:7738647
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项目类别:
-
资助金额:$35.88万
-
财政年份:2009
-
负责人:GREGORIO GIL
-
依托单位:
Regulation of Bile Acid Synthesis by Nuclear Receptors in Vivo
-
批准号:8029563
-
项目类别:
-
资助金额:$31.87万
-
财政年份:2009
-
负责人:GREGORIO GIL
-
依托单位:
Regulation of Bile Acid by an alpha 1-AT Peptide
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批准号:7080373
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项目类别:
-
资助金额:$33.65万
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财政年份:2003
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负责人:GREGORIO GIL
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依托单位:
Regulation of Bile Acid by an alpha 1-AT Peptide
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批准号:6798146
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项目类别:
-
资助金额:$34.49万
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财政年份:2003
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负责人:GREGORIO GIL
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依托单位:
Regulation of Bile Acid by an alpha 1-AT Peptide
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批准号:6935804
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项目类别:
-
资助金额:$34.47万
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财政年份:2003
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负责人:GREGORIO GIL
-
依托单位:
Regulation of Bile Acid by an alpha 1-AT Peptide
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批准号:7252100
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项目类别:
-
资助金额:$32.66万
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财政年份:2003
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负责人:GREGORIO GIL
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依托单位:
CHOLESTEROL 7ALPHA-HYDROXYLASE IN TRANSGENIC MICE
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批准号:2143621
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项目类别:
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资助金额:$12.34万
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财政年份:1991
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负责人:GREGORIO GIL
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依托单位:
CHOLESTEROL 7ALPHA-HYDROXYLASE IN TRANSGENIC MICE
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批准号:3245744
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项目类别:
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资助金额:$10.26万
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财政年份:1991
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负责人:GREGORIO GIL
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依托单位:
REGULATION OF CHOLESTEROL 7 ALPHA-HYDROXYLASE
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批准号:2143623
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项目类别:
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资助金额:$19.95万
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财政年份:1991
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负责人:GREGORIO GIL
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依托单位:
REGULATION OF CHOLESTEROL 7 ALPHA-HYDROXYLASE
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批准号:2143624
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项目类别:
-
资助金额:$6.47万
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财政年份:1991
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负责人:GREGORIO GIL
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依托单位:
REGULATION OF CHOLESTEROL 7 ALPHA HYDROXYLASE
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批准号:2518308
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项目类别:
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资助金额:$18.98万
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财政年份:1991
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负责人:GREGORIO GIL
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依托单位:
REGULATION OF CHOLESTEROL 7 ALPHA HYDROXYLASE
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批准号:2454684
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项目类别:
-
资助金额:$13.02万
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财政年份:1991
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负责人:GREGORIO GIL
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依托单位:
CHOLESTEROL 7ALPHA-HYDROXYLASE IN TRANSGENIC MICE
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批准号:3245742
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项目类别:
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资助金额:$15.34万
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财政年份:1991
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负责人:GREGORIO GIL
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依托单位:
REGULATION OF CHOLESTEROL 7 ALPHA HYDROXYLASE
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批准号:2770398
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项目类别:
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资助金额:$19.0万
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财政年份:1991
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负责人:GREGORIO GIL
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依托单位:
海外基金