Genetic and molecular mechanisms for statin-induced myopathy and dysglycemia in the mouse

他汀类药物诱发的小鼠肌病和血糖异常的遗传和分子机制

• 批准号: 9139488
• 负责人: Karen Reue
• 金额: $ 52.55万
• 依托单位: CHILDREN'S HOSPITAL & RES CTR AT OAKLAND
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9139488
• 关键词: Adverse effects; Affect; Autophagocytosis; Beta Cell; Candidate Disease Gene; Cell Line; Cell physiology; Cholesterol; Chromosome Mapping; Collaborations; Control Locus; Creatine Kinase; Diabetes Mellitus; Diet; Drug Prescriptions; Drug user; Effectiveness; Environmental Risk Factor; Evaluation; Female; Fragile X Syndrome; Gene Expression; Genes; Genetic; Genetic Markers; Genetic Variation; Genotype; Guidelines; Histopathology; Homeostasis; Human; Human Cell Line; Human Genetics; Hybrids; Inbred Mouse; Inbred Strain; Individual; Inflammation; Informatics; Insulin Resistance; Measurement; Metabolism; Mitochondria; Modeling; Molecular; Molecular Analysis; Molecular Genetics; Molecular Profiling; Mouse Strains; Mus; Muscle; Muscle Cells; Myopathy; Non-Insulin-Dependent Diabetes Mellitus; Organelles; Osteoporosis; Pain; Patients; Pharmaceutical Preparations; Pharmacogenomics; Pharmacotherapy; Phenotype; Physiological; Predisposition; Proteins; Randomized Clinical Trials; Research Personnel; Resolution; Resources; Rett Syndrome; Rhabdomyolysis; Risk; Role; Safety; Signal Transduction; Staining method; Stains; Structure of beta Cell of islet; Symptoms; Testing; Tissues; Toxic effect; Translations; Weight Gain; Western World; Woman; Work; base; biomarker identification; blood glucose regulation; cardiovascular disorder risk; compliance behavior; genetic analysis; genetic association; genetic resource; genetic variant; genome wide association study; glucose metabolism; glucose tolerance; impaired glucose tolerance; in vivo; indexing; innovation; male; molecular marker; mouse model; muscle strength; novel; protein kinase D; sex; tool; trait; treatment duration

PROJECT 2: SUMMARY   Statins are among the most widely prescribed drugs in the western world, used to treat elevated cholesterol levels and reduce the risk of cardiovascular disease. While statins are highly effective and generally safe, adverse effects occur in a small proportion of users, which represents a large number of individuals due to statins' widespread use. In some individuals, statins adversely affect muscle, with symptoms ranging from mild pain to rhabdomyolysis. Recent studies have also shown a 9-12% increase in risk for type 2 diabetes among statin users. We hypothesize that many of the genetic variants and molecular mechanisms that influence statin-related myopathy and new-onset diabetes remain to be identified. In preliminary work, we have established that the mouse is a feasible model in which to identify genetic variation in statin-related muscle toxicity and dysglycemia, and it offers superior features for genetic and molecular analysis. In this Project, we will utilize a novel mouse genetics resource, the Hybrid Mouse Diversity Panel (HMDP), which consists of ~110 inbred mouse stains. We will use the HMDP to identify genes (Aim 1) and mechanisms (Aim 2) underlying statin-associated myotoxicity and diabetes. In Aim 3 we will perform in vivo studies in the mouse to validate selected genes identified in human studies in other projects within this Center. Innovative features of our approach include the ability to perform genetic association to high resolution in the HMDP, often to loci containing just a handful of genes. Additionally, our studies will include full HMDP sets of males and females, providing the opportunity to identify sex-specific statin effects. Our preliminary studies have identified effects of statins on protein kinase D signaling and autophagy in myocytes and beta cells, and we will elucidate these further at the physiological, cellular and molecular levels. These studies, together with the translation of human genetic variants to in vivo mouse models, will inform us about potential genetic and molecular markers that may be valuable for the evaluation of individual benefit versus risk of statin drug treatment.

项目2：摘要   他汀类药物是西方世界中规定的药物，用于治疗升高的胆固醇 水平并降低心血管疾病的风险。他汀类药物非常有效，通常是安全的，但 不利影响发生在一小部分用户中，这代表了大量个人 他汀类药物的宽度使用。在某些人中，他汀类药物不利地影响肌肉，符号从中间 横幅溶解疼痛。最近的研究还显示，2型糖尿病风险增加了9-12％ 他汀类药物用户。我们假设许多影响影响的遗传变异和分子机制 他汀类药物相关的肌病和新发育糖尿病仍有待确定。在初步工作中，我们有 确定小鼠是一个可行的模型，在该模型中，识别他汀类药物相关肌肉的遗传变异 毒性和血糖症，并为遗传和分子分析提供了出色的特征。在这个项目中，我们 将利用一种新型的鼠标遗传学资源，混合小鼠多样性面板（HMDP），由 〜110个近交小鼠污渍。我们将使用HMDP识别基因（AIM 1）和机制（AIM 2） 基础他汀类药物相关的肌毒性和糖尿病。在AIM 3中，我们将在小鼠中进行体内研究 验证该中心内其他项目的人类研究中确定的选定基因。创新的特征 我们的方法包括能够与HMDP中的高分辨率进行遗传关联的能力，通常 仅包含少数基因。此外，我们的研究将包括完整的HMDP雄性和 女性提供了识别特定性别汀类药物影响的机会。我们的初步研究已经确定 他汀类药物对肌细胞和β细胞中蛋白激酶D信号传导和自噬的影响，我们将阐明 这些在物理，细胞和分子水平上进一步。这些研究，以及翻译 人体遗传变异到体内小鼠模型，将告知我们有关潜在的遗传和分子标记 这对于评估个人福利与他汀类药物治疗的风险可能很有价值。