Physiological Dissection of the Mevalonate Pathway

甲羟戊酸途径的生理解剖

基本信息

批准号：
10579186
负责人：
William Raymond Lagor
金额：
$ 53.21万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-06 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10579186
关键词：
Ablation Acute Address Adult Adverse event Affect Alcohols Alleles Apoptosis Biological Assay CRISPR/Cas technology Cardiovascular Diseases Cells Cholesterol Clinical Clinical Drug Development Clustered Regularly Interspaced Short Palindromic Repeats Coenzyme A Crestor Data Development Dissection Dolichol Drug usage Enzymes Experimental Animal Model Functional disorder Gene Expression Genes Genetic Glycoproteins Goals Guidelines Health Heart Diseases Hepatocyte Hepatotoxicity Histology Human Induction of Apoptosis Investigation Knock-out Knockout Mice Knowledge Link Lipids Liquid Chromatography Liver Low-Density Lipoproteins Mass Chromatography Measures Metabolic Monitor Mus Non-Insulin-Dependent Diabetes Mellitus Oxidoreductase Pathologic Pathway interactions Pharmaceutical Preparations Physiological Physiology Plasma Pravastatin Protein Farnesylation Protein Geranylgeranylation Rattus Reaction Regulation Research Resistance Risk Risk Reduction Role Route Severities Simvastatin Testing Time Toxic effect Transfer RNA Transplantation Ubiquinone United States Up-Regulation Viral Vitamin K Vitamin K 2 Western Blotting Whole Organism adeno-associated viral vector adverse event risk atorvastatin blood glucose regulation clinically relevant conditional knockout drug action endoplasmic reticulum stress experience farnesylation genetic manipulation genome editing glycosylation heme a improved in vivo individual variation isoprenoid lipid metabolism liver function mevalonate mortality risk new therapeutic target overexpression personalized medicine protein K response rosuvastatin scaffold tool transcriptome sequencing transmission process zocor

项目摘要

PROJECT SUMMARY Statins are the only lipid lowering agents consistently shown to reduce the risk of death from cardiovascular disease as a monotherapy. Currently, it is estimated that greater than 39.2 million adults in the United States are on statins, and new may further increase the number of users in the U.S. alone to 56.0 million. This underscores the importance of understanding the genetic basis of statin responsiveness as well as adverse events. Statins act primarily in the liver by inhibiting 3-hydroxy-3-methylglutaryl Coenzyme A reductase (Hmgcr), the rate-limiting enzyme in the mevalonate pathway. In addition to cholesterol, the mevalonate pathway also produces other essential molecules including: isopentenyl tRNA, heme A, ubiquinone, dolichol, farnesylated and geranylgeranylated proteins, and vitamin K2. Despite over three decades of research, development, and clinical experience with statins, many unanswered questions remain about the physiological role and regulation of the mevalonate pathway in the liver. Critical gaps in knowledge include: 1) which nonsterol metabolites are most sensitive to depletion, 2) the necessity of the different mevalonate-derived metabolites for hepatocyte function, 3) the precise identity of nonsterol regulatory molecules, 4) genetic factors that determine individual variation in LDL-C lowering, and 5) the mechanisms by which statins increase the risk of type II diabetes. Our long-term goal is understand the physiological mechanisms controlling the mevalonate pathway and statin responsiveness, in order to enable personalized medicine and identify new drug targets. We propose three Specific Aims: 1) Define which isoprenoid products are required for hepatocyte viability in vivo, 2) Test the hypothesis that loss of dolichol is responsible for ER stress-induced apoptosis during potent Hmgcr inhibition, 3) Determine the physiological effects of statins on human hepatocytes in vivo. Successful completion of these studies will define the essential mevalonate-derived metabolites in the liver, and improve our understanding of new genes and pathways underlying statin-related hepatotoxicity and statin responsiveness.

项目摘要他汀类药物是唯一始终显示出来降低心血管死亡风险的脂质降低剂疾病是一种单一疗法。目前，据估计，美国超过3920万成年人在他汀类药物上，新的可能仅将美国的用户数量增加到560万。这突显了了解他汀类药物反应性和不良事件的遗传基础的重要性。他汀类药物主要通过抑制3-羟基-3-甲基戊二酰辅酶A还原酶（HMGCR）（HMGCR）作用于肝脏。在甲谷酸盐途径中的酶。除胆固醇外，甲谷酸酯途径还产生其他必需分子包括：等原烯基tRNA，血红素A，泛氨基酮，多利果醇，法尔替酯和黄烷基凝集烯基蛋白和维生素K2。尽管进行了三十年的研究，发展和临床他汀类药物的经验，关于生理作用和调节的许多未解决的问题仍然存在肝脏中的甲瓦隆河道。知识的关键差距包括：1）哪种非代谢物是最多的对耗竭敏感，2）不同甲戊酸衍生的代谢物的肝细胞功能的必要性， 3）非固醇调节分子的精确身份，4）决定个体变化的遗传因素 LDL-C降低，以及5）他汀类药物增加II型糖尿病风险的机制。我们的长期目标了解控制Mevalonate途径和他汀类药物反应的生理机制，为了实现个性化医学并确定新药物靶标。我们提出了三个具体目标：1）定义在体内肝细胞生存能力需要哪种类异戊二烯产物，2）检验dolichol丢失的假设在有效的HMGCR抑制期间负责ER应力诱导的凋亡，3）确定生理他汀类药物对体内人类肝细胞的影响。这些研究的成功完成将定义重要的肝脏中的大甲酸盐代谢物，并提高我们对新基因和途径的理解基本的他汀类药物相关的肝毒性和他汀类药物的反应性。