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Targeting the orphan nuclear receptor LRH-1 with small molecules

用小分子靶向孤儿核受体 LRH-1

基本信息

批准号：
10660545
负责人：
John Winter Calvert
金额：
$ 56.93万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10660545
关键词：
Address Adipose tissue Affinity Agonist American Antidiabetic Drugs Atherosclerosis Award Behavior Bile Acids Binding Binding Sites Biological Biological Assay Biological Availability Biology CRISPR/Cas technology Cardiovascular Diseases Characteristics Charge Chemicals Chemistry Clinical Development Diabetes Mellitus Disease Dose Drug Kinetics Epidemic Exposure to Fatty Acids Fatty acid glycerol esters Gene Expression Generations Glucose Health Homeostasis Human Insulin Insulin Resistance Knowledge Lead Ligand Binding Ligands Lipids Liver Measures Metabolic Metabolic Diseases Metabolic Pathway Modeling Modification Monitor Mus Myocardial Infarction NR5A2 gene Non-Insulin-Dependent Diabetes Mellitus Nuclear Hormone Receptors Nuclear Orphan Receptor Obese Mice Obesity Oral cavity Overnutrition Overweight Pharmacodynamics Pharmacology Phospholipids Plasma Proteins Proteomics Research Risk Rodent Rodent Model Series Stroke Structure Structure-Activity Relationship Surface Testing Therapeutic Therapeutic Agents Tissues United States Work biophysical properties comorbidity design diet-induced obesity dietary efficacy evaluation fatty liver disease glucose metabolism glucose tolerance humanized mouse improved in vivo innovation insight insulin sensitivity lipid metabolism lipidomics lipophilicity liquid chromatography mass spectrometry liver function mRNA Expression mortality risk mouse model new therapeutic target non-alcoholic fatty liver disease novel pre-clinical preclinical study reverse cholesterol transport small molecule success tool transcriptome transcriptome sequencing

项目摘要

PROJECT SUMMARY Obesity is a growing epidemic in the United States, leading to increases in cases of nonalcoholic fatty liver disease (NAFLD), cardiovascular disease, and type II diabetes. A common characteristic of these diseases is aberrant lipid and glucose metabolism. This proposal centers on the nuclear hormone receptor, Liver Receptor Homolog 1 (LRH-1), which acts as an important regulator of lipid metabolism, reverse cholesterol transport, glucose sensing, and homeostasis. As such, LRH-1 represents a novel therapeutic target for metabolic diseases. LRH-1 binds to phospholipids (PLs) and is activated by the unusual PL dilauroylphosphatidylcholine (DLPC) which shows potent anti-diabetic effects. The discovery that LRH-1 is regulated by PL ligands reveals an exciting potential to tune LRH-1 activity for the treatment of metabolic diseases. However, PLs are labile and not suitable for clinical use, necessitating the development of small molecule agonists. This has proved challenging thus far, since very few small molecules can displace endogenous lipids from the large, lipophilic binding pocket. Recent studies in our lab have characterized a class of small molecules that are capable of this feat. Using robust SAR and innovative chemistry, we have designed potent LRH-1 agonists that display biological activity. We have modified our most potent and efficacious agonists to improve their biophysical properties, making them suitable for in vivo studies. The advancement of LRH-1 agonists as therapeutics has also been hindered by the lack of appropriate rodent models to screen potential candidates due to small sequence differences in the binding pocket of rodent and human LRH-1. To overcome this barrier, we used a CRISPR-Cas9 strategy to humanize the mouse LRH-1 ligand binding pocket. This permits activation by synthetic agonists while minimizing changes to endogenous interaction surfaces. These leaps forward in lead compound development and mouse model generation, in combination with our deep knowledge of LRH-1 structure and function, create an ideal platform to develop candidate preclinical LRH-1 modulators for metabolic disease. Here, we have developed a strategy to define mechanisms of action, target engagement, pharmacology, and disease efficacy of our lead compounds. In aim 1, we generate compounds with improved biophysical properties that mimic PL-like activation. We will perform mechanistic characterization of these compounds to explore how contacting the PL-binding site with different polar moieties improves LRH-1 activation. In aim 2, we will examine the behavior of our lead compounds from an ADME perspective. The primary objective will be to establish tractability of the compounds using our humanized mice, so that pharmacokinetic relationships can be established. In aim 3, we will use our humanized mice and a model of diet-induced obesity to evaluate the in vivo efficacy of our lead LRH-1 compounds to improve glucose tolerance and insulin resistance.

项目总结

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The Rho-GEF PIX-1 directs assembly or stability of lateral attachment structures between muscle cells.

DOI：
10.1038/s41467-020-18852-4
发表时间：
2020-10-06
期刊：
Nature communications
影响因子：
16.6
作者：
Moody JC;Qadota H;Reedy AR;Okafor CD;Shanmugan N;Matsunaga Y;Christian CJ;Ortlund EA;Benian GM
通讯作者：
Benian GM

Hydrogen sulfide regulates cardiac mitochondrial biogenesis via the activation of AMPK.

DOI：
10.1016/j.yjmcc.2018.01.011
发表时间：
2018-03
期刊：
Journal of molecular and cellular cardiology
影响因子：
5
作者：
Shimizu Y;Polavarapu R;Eskla KL;Nicholson CK;Koczor CA;Wang R;Lewis W;Shiva S;Lefer DJ;Calvert JW
通讯作者：
Calvert JW

Structural insights into glucocorticoid receptor function.