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：
8214499
负责人：
THOMAS J LYONS
金额：
$ 24.51万
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/8214499
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 Diet 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）：黄体酮是一种具有巨大生理重要性的类固醇激素。它不仅在生殖中发挥核心作用，而且还具有神经活性特性。在生物系统中模拟或调节黄体酮（孕激素和抗孕激素）作用的分子具有重要的药学重要性，最常用于节育以及治疗癌症和子宫内膜异位症。传统上，此类分子的生物活性是通过研究它们对经过深入研究的核孕酮受体的影响来测试的，并且仅从这个角度来解释它们在人体中的影响。最近，发现了一类新的孕酮受体，它们位于质膜上，这些受体很可能代表孕酮样分子的另一个体内靶点。因此，这些膜孕酮受体的表征可能会更清楚地描绘孕酮的生理学和孕酮样化合物的药理学。在该提案中，将开发一种测定系统，用于研究这种新型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类孕酮受体来实现。该系统的优点是能够功能性地表达这些受体，并且不具有可能干扰单个人膜孕酮受体分析的其他孕酮结合蛋白。该系统将首先用于探测这些新受体的结构方面与其结合孕酮和在细胞内转导信号的能力之间的关系。这些膜孕酮受体感知细胞外孕酮并产生细胞内第二信使，负责细胞内的生理变化。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具有药物、饮食和环境重要性的化合物，以确定它们激活或抑制该特定类别受体的能力。这些实验将显着扩大我们对黄体酮生物学以及黄体酮类药物的药理学和潜在副作用的理解。公众健康启示：类固醇激素、黄体酮和调节其作用的分子具有至关重要的制药和环境重要性。我们已经建立了一个系统，通过该系统我们可以研究这些分子如何影响一个新的激素受体家族，而这在很大程度上尚未被研究。该提案中概述的研究将显着扩大我们对人类细胞如何感知和响应类固醇激素的理解。