Biochemical and pharmacological studies of human membrane progesterone receptors

人膜孕酮受体的生化和药理学研究

基本信息

批准号：
8019106
负责人：
THOMAS J LYONS
金额：
$ 24.44万
依托单位：
FOUNDATION FOR APPLIED MOLECULAR EVOLUTN
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-02-01 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8019106
关键词：
Accounting Address Adverse effects Affect Agonist Anti-Progestin Barbiturates Binding Biochemical Biochemistry Biological Biological Assay Biological Availability Biological Models Biology Cell membrane Cells Chemicals Classification Contraceptive methods Drug Prescriptions Elements Emergency Situation Estrogens Event Family Fishes G-Protein-Coupled Receptors Gene Expression Genetic Transcription Genomics Goals Half-Life Homologous Protein Hormone Receptor Hormones Human Human body Individual Integral Membrane Protein Intracellular Second Messenger Intracellular Signaling Proteins Lead Libraries Ligand Binding Ligands Light Mediating Membrane Modeling Moods Names Nuclear Organism Paint Pathway interactions Pharmaceutical Preparations Pharmacologic Substance Pharmacology Physiological Physiology Play Progesterone Progesterone Receptors Progesterone-Binding Globulin Progestins Property Protein Binding Proteins Public Health Reproduction Research Personnel Role Saccharomyces cerevisiae Second Messenger Systems Signal Pathway Signal Transduction Sphingolipids Steroids Structure Structure-Activity Relationship Study models System Testing Uncertainty Vertebrates Yeasts activating transcription factor barbituric acid salt base biological systems birth control cancer therapy design endometriosis extracellular in vivo neurosteroids non-genomic novel receptor receptor function research study response second messenger steroid hormone

项目摘要

DESCRIPTION (provided by applicant): Progesterone is a steroid hormone of tremendous physiological importance. Not only does it play a central role in reproduction, but it also has neuroactive properties. Molecules that mimic or modulate the effects of progesterone (progestins and antiprogestins) in biological systems are of significant pharmaceutical importance, being most commonly used for birth control and in the treatment of cancer and endometriosis. Traditionally, the biological activity of such molecules has been tested by investigating their effects on the well studied nuclear progesterone receptor and their effects in the human body have been interpreted solely in this light. Recently, a new class of receptors for progesterone has been discovered that reside on the plasma membrane and it is likely that these receptors represent an additional in vivo target for progesterone-like molecules. Consequently, the characterization of these membrane progesterone receptors is likely to paint a clearer picture of the physiology of progesterone and the pharmacology of progesterone-like compounds. In this proposal, an assay system will be developed with which the biochemistry and pharmacology of this new class of progesterone receptor can be investigated. This will be achieved by expressing the human progesterone receptors in a simple model system called Saccharomyces cerevisiae. This system has the benefit of being able to functionally express these receptors and of not possessing other progesterone binding proteins that can interfere with analysis of the individual human membrane progesterone receptors. This system will first be used to probe the relationship between the structural aspects of these new receptors and their ability to bind progesterone and transduce signals inside cells. These membrane progesterone receptors sense extracellular progesterone and produce an intracellular second messenger that is responsible for the physiological changes inside cells. However, the identity of the second messenger produced by these receptors is unknown. Therefore, the second goal of this proposal will consist of identifying the chemical mechanism of signal transduction. Finally, the system can be used to screen large numbers of chemical compounds of pharmaceutical, dietary and environmental importance for their ability to activate or inhibit receptors in this particular class. These experiments will significantly expand our understanding of the biology of progesterone as well as the pharmacology and potential side-effects of progesterone-like pharmaceuticals. PUBLIC HEALTH REVELANCE: The steroid hormone, progesterone, and molecules that modulate its effects are of critical pharmaceutical and environmental importance. We have established a system through which we can investigate how such molecules affect a new family of hormone receptors that is largely unstudied. The studies outlined in this proposal will significantly expand our understanding of how human cells sense and respond to steroid hormones.

描述（由申请人提供）：孕酮是一种非常重要的类固醇激素。它不仅在繁殖中起着核心作用，而且具有神经活性的特性。模仿或调节孕激素（孕激素和抗脂蛋白）在生物系统中的作用的分子具有重要的药物重要性，最常用于避孕药以及治疗癌症和子宫内膜异位症。传统上，这种分子的生物学活性通过研究了它们对所研究良好的核孕激素受体的影响，并且它们在人体中的作用仅在这种情况下被解释。最近，已经发现了一种驻留在质膜上的新型孕激素受体，这些受体很可能代表了孕酮样分子的额外体内靶标。因此，这些膜孕酮受体的表征可能会更清晰地描绘孕酮生理学和类似孕酮的化合物的药理学。在此提案中，将开发一种测定系统，可以研究这种新的孕酮受体的生物化学和药理学。这将通过在称为酿酒酵母的简单模型系统中表达人孕酮受体来实现。该系统的好处是能够在功能上表达这些受体，并且没有其他可以干扰对单个人膜孕激素受体分析的孕酮结合蛋白。该系统将首先用于探测这些新受体的结构方面与结合孕激素和传播信号在细胞内的能力之间的关系。这些膜孕激素受体会感知细胞外孕酮，并产生一个细胞内第二信使，该信使负责细胞内部的生理变化。然而，这些受体产生的第二信使的身份尚不清楚。因此，该提案的第二个目标将包括确定信号转导的化学机制。最后，该系统可用于筛选大量药物，饮食和环境重要性的化合物，以激活或抑制该特定类别的受体的能力。这些实验将显着扩展我们对孕酮生物学以及类似孕激素的药理学和潜在副作用的理解。公共卫生的启示：调节其作用的类固醇激素，孕酮和分子至关重要的药物和环境重要性。我们已经建立了一个系统，我们可以通过该系统研究这种分子如何影响很大程度上未研究的新的激素受体家族。该提案中概述的研究将大大扩展我们对人类细胞感和对类固醇激素的反应的理解。