Nuclear Lipids in Steroidogenesis

类固醇生成中的核脂质

基本信息

批准号：
8639551
负责人：
Marion B. Sewer
金额：
$ 24.82万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
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：
2010-05-24 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8639551
关键词：
Address Adrenal Cortex Adrenal Glands Agonist Anabolism Androgens Binding Biochemical Biological Assay CYP17A1 gene Catabolism Cell Nucleus Cell membrane Cells Ceramidase Chromatin Complex Corticotropin Cyclic AMP Data Development Diacylglycerol Kinase Dissociation Endocrine System Diseases Ensure Environment Enzymes Gene Expression Gene Expression Regulation Genes Genetic Transcription Goals Homeostasis Hormones Human Hydrocortisone Knowledge Ligand Binding Ligands Lipids Mediating Metabolic Metabolism Microscopic Molecular Nuclear Nuclear Envelope Nuclear Receptors Phosphatidic Acid Phospholipid Metabolism Phospholipids Phosphorylation Physiological Processes Pituitary Gland Pituitary-dependent Cushing&apos s disease Play Polycystic Ovary Syndrome Post-Translational Protein Processing Process Production Property Proteins RNA Processing Receptor Activation Regulation Reproduction Research Role SF1 Sex Characteristics Signal Pathway Signal Transduction Site-Directed Mutagenesis Sodium Sphingolipids Sphingosine Steroid biosynthesis Sum Testing Tissues Transactivation Transcriptional Activation Work adrenal hyperplasia base cell type chromatin immunoprecipitation enzyme activity galactosylgalactosylglucosylceramidase insight mRNA Export novel peptide hormone protein protein interaction public health relevance receptor receptor function research study response sphingosine 1-phosphate steroid hormone steroid hormone biosynthesis tandem mass spectrometry

项目摘要

DESCRIPTION (provided by applicant): Steroid hormones are key regulators of a diverse array of physiological processes, including sodium homeostasis, reproduction, and the development of secondary sex characteristics. These molecules allow tissues to respond in a coordinated manner to changes in the internal and external environments by functioning as ligands for both nuclear and plasma membrane receptors. Because steroid hormones control the expression of numerous genes in virtually all cell types, steroidogenic cells utilize multiple mechanisms that ensure tight control of the synthesis of these molecules. A major goal of our research is to understand the mechanisms by which the pituitary-derived hormone adrenocorticotropin (ACTH) regulates cortisol production by the adrenal cortex. Our research has identified a key role for bioactive sphingolipids and phospholipids. These molecules control hormone production by controlling the transcription of steroidogenic genes. We hypothesize that ACTH controls steroid hormone biosynthesis by modulating the availability of bioactive sphingolipids and phospholipids in the nuclei of adrenocortical cells. Specific Aim 1 will define the capacity for nuclear sphingolipid and phospholipid metabolism. Preliminary data has established that bioactive phospholipids and sphingolipids control steroidogenic gene transcription by serving as ligands for the nuclear receptor steroidogenic factor-1 (SF-1). Since is primarily localized in the nucleus, we hypothesize that locally synthesized bioactive lipids are key for controlling SF-1 function. Lipid profiling will be used to gain a comprehensive and quantitative assessment of the concentrations of sphingolipid and phospholipid species in the nucleus and the effect of ACTH on the amounts of these lipids. Specific Aim 2 determine the mechanism by which acid ceramidase (encoded by ASAH1b) regulates nuclear SPH concentrations and SF-1 function. ASAH1b is one of three ceramidases that produces sphingosine (SPH). We have evidence to support a role for direct interaction between ASAH1b and SF-1 and for the regulation of ASAH1 function by phosphorylation. We will investigate the role of this enzyme as a SF-1 coregulatory protein. Specific Aim 3 will define the mechanism by which activation of cAMP signaling promotes ligand (PA)-dependent activation of steroidogenic gene expression. Increased steroidogenic gene expression occurs with the binding agonist ligand (phosphatidic acid) to SF-1 and the subsequent activation of transcription. Tandem mass spectrometry and enzymatic assays will be used to define the role of posttranslational modification in controlling the activity of enzymes that synthesize phosphatidic acid. In sum this proposal addresses major questions about the mechanisms underlying gene regulation by locally produced bioactive lipids. The knowledge gained from these studies will provide valuable information about the metabolic capacity of the nucleus and the key role that dynamic flux of bioactive lipids plays in the control of gene expression.

描述（由申请人提供）：类固醇激素是多种生理过程的关键调节剂，包括钠稳态、生殖和第二性征的发育。这些分子通过充当核和质膜受体的配体，使组织能够以协调的方式响应内部和外部环境的变化。由于类固醇激素控制几乎所有细胞类型中众多基因的表达，类固醇生成细胞利用多种机制来确保严格控制这些分子的合成。我们研究的一个主要目标是了解垂体衍生激素促肾上腺皮质激素 (ACTH) 调节肾上腺皮质产生皮质醇的机制。我们的研究已经确定了生物活性鞘脂和磷脂的关键作用。这些分子通过控制类固醇生成基因的转录来控制激素的产生。我们假设 ACTH 通过调节肾上腺皮质细胞核中生物活性鞘脂和磷脂的可用性来控制类固醇激素的生物合成。具体目标 1 将定义核鞘脂和磷脂代谢的能力。初步数据表明，生物活性磷脂和鞘脂通过作为核受体类固醇生成因子 1 (SF-1) 的配体来控制类固醇生成基因转录。由于主要位于细胞核，我们假设局部合成的生物活性脂质是控制 SF-1 功能的关键。脂质分析将用于对细胞核中鞘脂和磷脂种类的浓度以及 ACTH 对这些脂质含量的影响进行全面和定量的评估。具体目标 2 确定酸性神经酰胺酶（由 ASAH1b 编码）调节核 SPH 浓度和 SF-1 功能的机制。 ASAH1b 是产生鞘氨醇 (SPH) 的三种神经酰胺酶之一。我们有证据支持 ASAH1b 和 SF-1 之间的直接相互作用以及通过磷酸化调节 ASAH1 功能。我们将研究这种酶作为 SF-1 辅助调节蛋白的作用。具体目标 3 将定义 cAMP 信号传导激活促进配体 (PA) 依赖性类固醇生成基因表达激活的机制。激动剂配体（磷脂酸）与 SF-1 的结合以及随后的转录激活会增加类固醇生成基因的表达。串联质谱和酶测定将用于确定翻译后修饰在控制合成磷脂酸的酶活性中的作用。总之，该提案解决了有关本地产生的生物活性脂质基因调控机制的主要问题。从这些研究中获得的知识将提供有关细胞核代谢能力以及生物活性脂质动态通量在基因表达控制中所起关键作用的有价值的信息。