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Estrogen Receptor Coligand Reprogramming of Menopausal Hormone Therapy

更年期激素治疗的雌激素受体辅配体重编程

基本信息

批准号：
9140165
负责人：
DALE C LEITMAN
金额：
$ 18.01万
依托单位：
IATERION, INC.
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-25 至 2017-09-24
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9140165
关键词：
Abdomen Adverse event Alzheimer&apos s Disease Animals Binding Binding Sites Blood Breast Breast Cancer Cell Cell Count Cell Culture Techniques Cell Line Cell Proliferation Cells Chronic Chronic Disease Clinical Research Combined Modality Therapy Complex Cultured Cells Data Development Diabetes Mellitus Drug Combinations Drug Kinetics Endometrial Carcinoma Estradiol Estriol Estrogen Receptor alpha Estrogen Receptors Estrogens Estrone Ethinyl Estradiol Event Exposure to Fatty acid glycerol esters Female Flow Cytometry Fracture Gene Expression Genes Goals Growth Health Hot flushes Incidence Lead Life Life Expectancy Ligands Longevity MCF7 cell Mammary gland Measures Mediating Menopause Metabolic Metabolic syndrome Molecular Conformation Molecular Models Mus Myocardial Infarction Non-Insulin-Dependent Diabetes Mellitus Obesity Oncogene Activation Osteitis Osteoporosis Osteoporosis prevention Pharmaceutical Preparations Pharmacodynamics Phase Ploidies Postmenopause Prevention Primary Prevention Production Proliferation Marker Raloxifene Regimen Risk Safety Selective Estrogen Receptor Modulators Serum Markers Stroke Surface Symptoms Temperature Testing Tissues Uterus Vagina Vulva Weight Weight Gain Woman Women&apos s Health base bone bone cell cancer cell cancer risk cardiovascular risk factor diabetes risk hormone therapy improved in vivo inflammatory marker innovation interest malignant breast neoplasm melting molecular modeling novel prevent public health relevance research clinical testing

项目摘要

DESCRIPTION (provided by applicant): Our goal is to discover drugs that will make menopausal hormone therapy (MHT) safe for long-term treatment of chronic conditions associated with menopause. Due to the increasing longevity of women, menopause has become a critical issue in Women's Health. Life expectancy for women is now 81.2 years. Unlike just a century ago, most women will reach menopause and live approximately one-third of their life after menopause. There are currently 36 million menopausal women in the U.S. and the number is projected to soar to about 50 million in 25 years. Unfortunately, menopause is associated with an increase in the incidence of osteoporosis, obesity, diabetes and metabolic syndrome. Long term exposure to MHT decreases the risk of these conditions. MHT is approved for short-term treatment of hot flashes and vaginal/vulvar symptoms, since long-term treatment with MHT is associated with an increased risk of breast cancer, cardiovascular risks and Alzheimer's disease. A major breakthrough in primary prevention for Women's Health would occur if safer MHT regimens could be developed for long-term treatment. We discovered compounds termed ERα coligands that reprogram the effects of estradiol on gene expression and cell proliferation. Our data indicate that the ERα coligand binds to the surface of ERα, at a separate binding site than estrogens, leading to an increase in binding of E2 to its binding site. The binding of both ligands simultaneously to ERα produces a change in conformation as demonstrated by an alteration in the melting temperature of ERα. These studies indicate that the conformation of the E2-ERα-ER coligand complex is distinct from the E2-ERα complex leading to the reprogramming of the E2 transcriptional and cellular effects. In fact, we found that the E2/ERα coligand combination reprograms E2 to regulate over 800 unique genes in U2OS cells. These genes are not regulated by E2 or the ERα coligand alone. It is well established that E2 stimulates the proliferation of MCF-7 breast cancer cells by binding to ERα resulting in the activation of oncogenes, such as c-MYC. We found that the ERα coligand reprograms ERα so E2 no longer causes cell proliferation, nor does it stimulate c-MYC production. The ERα coligand also blocked E2 stimulation of uterine growth in mice. Based on these findings, we hypothesize that ERα coligands can be combined with existing estrogens, used in MHT, to block the adverse proliferative action of E2 to allow the ERα coligand/estrogen combination to be used safely for long-term MHT treatment. The aim of this phase I proposal is to select a lead ERα coligand/estrogen combination that has the best safety profile in cultured cells and animals prior to advancing it to Pharmacokinetic/Pharmacodynamic and other pre-clinical testing in a phase II proposal. These studies have the potential to facilitate the early development of a new type of MHT, that can be used for long-term administration, to prevent chronic diseases associated with menopause, such as osteoporosis, obesity, diabetes and metabolic syndrome.