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Physiological Dissection of the Mevalonate Pathway

甲羟戊酸途径的生理解剖

基本信息

批准号：
10359805
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 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10359805
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 Dissection Dolichol Drug usage Enzymes Experimental Animal Model Functional disorder Gene Expression Genes Genetic Glycoproteins Goals Guidelines Health Heart Diseases Hepatocyte Hepatotoxicity Histology Human 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 Proteins Rattus Reaction Regulation Research Resistance Risk Role Route Severities Simvastatin Testing Time Toxic effect Transfer RNA Transplantation Ubiquinone United States Up-Regulation Vitamin K Vitamin K 2 Western Blotting Whole Organism adeno-associated viral vector adverse event risk atorvastatin blood glucose regulation clinically relevant conditional knockout endoplasmic reticulum stress experience 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 research and development 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.

项目总结