Optimal Selective Thyroid Hormone Analogs for Metabolic Syndrome

用于代谢综合征的最佳选择性甲状腺激素类似物

基本信息

批准号：
8045787
负责人：
Paul Webb
金额：
$ 292.15万
依托单位：
METHODIST HOSPITAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-30 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8045787
关键词：
Address Affect Affinity Animal Model Animals Atherosclerosis Binding Biological Assay Biotechnology Blood Glucose Body fat Cardiovascular Diseases Catabolism Cell Culture Techniques Chemistry Cholesterol Data Data Reporting Death Rate Development Diabetic mouse Disease Dose Dyslipidemias Effectiveness Epidemic Exhibits Fatty Liver Fatty acid glycerol esters Future GC 1 compound Gene Expression Generations Genes Genomics Head Health Heart Rate High Density Lipoprotein Cholesterol High Density Lipoproteins Hormones Human In Vitro Incidence Insulin Resistance LDL Cholesterol Lipoproteins Learning Life Style Ligands Lipids Lipoprotein (a)Liver Liver diseases Low-Density Lipoproteins Metabolic Diseases Metabolic syndrome Metabolism Mouse Cell Line Muscle Myocardium Non-Insulin-Dependent Diabetes Mellitus Nuclear Receptors Obesity Obesity associated disease Pathway interactions Patients Pharmaceutical Preparations Pharmacologic Substance Plasma Play Primates Property Protein Isoforms Proteins Public Domains Research Personnel Rodent Model Role Serum Staging Structure System Testing Thyroid Hormone Receptor Thyroid Hormones Tissues Triglycerides United States Weight Western World Work X-Ray Crystallography analog base bone chemical property combat comparative hormone analog improved innovation insulin sensitivity mortality mouse model non-alcoholic non-alcoholic fatty liver nonalcoholic steatohepatitis novel pre-clinical preclinical study prevent receptor reverse cholesterol transport structural biology success uptake

项目摘要

DESCRIPTION (provided by applicant): The combined threat of cardiovascular disease (CVD) and obesity is arguably the worst major health problem affecting the western world. While there has been progress in reducing CVD mortality, death rates remain unacceptably high. Current approaches to treatment of obesity and associated diseases such as T2DM have not reduced the epidemics; in spite of aggressive efforts to modify lifestyles in the United States; success will require many years. It is essential to develop innovative treatments for these disorders. Nuclear receptors (NRs) are one of the most important classes of regulatory molecules and major targets for pharmaceuticals. Thyroid hormones (THs) and their cognate nuclear receptors (TRs 1 and 2) are master regulators of metabolism. While TH excess leads to deleterious effects such as elevated heart rate, arrythmias and muscle and bone catabolism there are beneficial effects such as reduced cholesterol and fat loss. Our team successfully developed ways to create selective TR modulators (STRMs) to safely elicit beneficial effects of TH excess states without harmful effects and several biotechnology companies have created compounds based on these principles. The STRMs have shown great promise for treatment of metabolic disease in preclinical animal models, where they variously reverse dyslipidemias, promote reverse cholesterol transport, reduce body fat in rodent models of obesity and primates, reduce liver fat in rodent models of non-alcoholic hepatic steatosis and improve insulin sensitivity in diabetic mice without obvious harmful effects. At least three of these compounds have been in human trials, with very promising results for treatment of high low density lipoprotein (LDL) cholesterol and elevations in other atherogenic serum lipids. We now realize, however, that existing STRMs exhibit distinctive combinations of different modes of selectivity; preferential binding to the TR2-isoform versus TR1, liver and tissue uptake selectivity and gene selectivity. We do not know which STRM is best for particular indications, what combination of selective effects is most desirable and whether the same or different combinations of selective actions are needed to treat different aspects of CVD and metabolic disorders. It is often hard to compare different compounds because data has not entered the public domain. In this study, we will define actions of existing STRMs and novel concept compounds and understand which aspects of their actions and properties will be most useful for different aspects of metabolic disease. Our strategy is to perform head to head comparisons of the existing and recently discovered ligands with distinct selectivity profiles and detailed analysis of mechanism in vitro, in cell culture and in well chosen mouse models of metabolic disease. Results will help fast-track the best of a potentially very useful group of compounds into tests in late-stage pre- clinical animal models and human trials and will help us define the best combination of selective actions for 2nd generation compounds. PUBLIC HEALTH RELEVANCE: Proteins called nuclear receptors play important roles in every major disease that affects the western world and many successful drugs already work through these proteins. We will find drugs that will safely treat high cholesterol and obesity and work through one class of these proteins, thyroid hormone receptors.

描述（由申请人提供）：心血管疾病（CVD）和肥胖的综合威胁可以说是影响西方世界的最严重的主要健康问题。虽然降低CVD死亡率的进展，但死亡率仍然不可接受。当前治疗肥胖症和相关疾病（例如T2DM）的方法尚未降低流行病。尽管为改变美国的生活方式做出了积极的努力；成功将需要多年。为这些疾病开发创新治疗至关重要。核受体（NRS）是最重要的调节分子和药物的主要靶标。甲状腺激素（THS）及其同源核受体（TRS 1和2）是代谢的主要调节剂。尽管过量会导致有害影响，例如心率升高，芳香族和肌肉和骨骼分解代谢，但胆固醇和脂肪减少等有益作用。我们的团队成功地开发了创建选择性TR调制器（Strm）的方法，以安全地产生过量状态的有益影响而没有有害影响，并且几家生物技术公司已经根据这些原则创建了化合物。 Strms在临床前动物模型中对治疗代谢疾病的治疗表现出了很大的希望，在临床前动物模型中，它们会逆转血脂异常，促进反向胆固醇的转运，减少肥胖模型和灵长类动物模型中的体内脂肪，减少脂肪脂肪模型中的肝脏脂肪模型，在非熟练脂肪剂的啮齿动物模型中，并改善糖尿病敏感性的胰岛素敏感性，而无需明显的有害效应。这些化合物中的至少三种是在人体试验中，对于高密度脂蛋白（LDL）胆固醇的治疗以及其他动脉粥样硬化血清脂质的升高的结果非常有希望。但是，我们现在意识到，现有的Strms表现出不同的选择性模式的独特组合。优先结合与TR2异型与TR1，肝脏和组织摄取选择性和基因选择性的结合。我们不知道哪种STRM最适合特定指示，选择性效应的哪种组合是最可取的，以及需要选择性作用的相同或不同组合来处理CVD和代谢性疾病的不同方面。通常很难比较不同的化合物，因为数据尚未进入公共领域。在这项研究中，我们将定义现有的Strm和新颖概念化合物的作用，并了解其作用和特性的哪些方面对于代谢疾病的不同方面最有用。我们的策略是对现有和最近发现的配体进行不同的选择性概况和详细分析的体外机理，细胞培养和精心选择的代谢疾病小鼠模型的详细分析。结果将有助于在后期临床动物模型和人类试验中快速进步，其中最有用的一组化合物组为测试，并将帮助我们定义第二代化合物的选择性作用的最佳组合。公共卫生相关性：称为核受体的蛋白质在影响西方世界的每种主要疾病中起着重要作用，许多成功的药物已经通过这些蛋白质起作用。我们将发现可以安全地治疗高胆固醇和肥胖的药物，并通过一类这些蛋白质甲状腺激素受体进行起作用。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（1）

Thyroid hormone receptor regulates most genes independently of fibroblast growth factor 21 in liver.

DOI：
10.1530/joe-14-0440
发表时间：
2015-03
期刊：
The Journal of endocrinology
影响因子：
0
作者：
Aijun Zhang;D. Sieglaff;J. P. York;J. Suh;S. Ayers;Glenn E. Winnier;A. Kharitonenkov;C. Pin;Pumin Zhang;P. Webb;Xuefeng Xia
通讯作者：
Aijun Zhang;D. Sieglaff;J. P. York;J. Suh;S. Ayers;Glenn E. Winnier;A. Kharitonenkov;C. Pin;Pumin Zhang;P. Webb;Xuefeng Xia

Thyroid hormone induction of human cholesterol 7 alpha-hydroxylase (Cyp7a1) in vitro.

DOI：
10.1016/j.mce.2014.02.003
发表时间：
2014-05-05
期刊：
Molecular and cellular endocrinology
影响因子：
4.1
作者：
Lammel Lindemann JA;Angajala A;Engler DA;Webb P;Ayers SD
通讯作者：
Ayers SD

A thyroid hormone receptor/KLF9 axis in human hepatocytes and pluripotent stem cells.

DOI：
10.1002/stem.1875
发表时间：
2015-03
期刊：
Stem cells (Dayton, Ohio)
影响因子：
0
作者：
Cvoro A;Devito L;Milton FA;Noli L;Zhang A;Filippi C;Sakai K;Suh JH;H Sieglaff D;Dhawan A;Sakai T;Ilic D;Webb P
通讯作者：
Webb P

Genome-wide binding patterns of thyroid hormone receptor beta.