Molecular mechanisms of steroid hormone secretion and trafficking

类固醇激素分泌和运输的分子机制

• 批准号: 8829315
• 负责人: Naoki Yamanaka
• 金额: $ 23.62万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8829315
• 关键词: ATP-Binding Cassette Transporters; Address; Adult; Affect; Animal Model; Appearance; Biochemistry; Biological Metamorphosis; Biological Models; Biology; Breast; Cell membrane; Cells; Cellular biology; Childhood; Clinical; Communication; Cues; Defect; Detection; Development; Diffuse; Diffusion; Disease; Drosophila genus; Drosophila melanogaster; Ecdysone; Educational process of instructing; Face; Family; G-Protein-Coupled Receptors; Gene Expression; Gland; Goals; Gonadal Steroid Hormones; Hair; Health; Hormones; Human; Immunohistochemistry; In Vitro; Insecta; Learning; Ligands; Malignant Neoplasms; Mammals; Mediating; Membrane; Mentors; Metabolic; Methods; Minnesota; Modeling; Molecular; Molecular Genetics; Molecular Profiling; Monitor; Movement; Nutritional; Organism; Outcome; Peripheral; Phase; Physiological; Physiological Processes; Physiology; Play; Procedures; Process; Puberty; RNA Interference; Research; Research Personnel; Role; Running; Sex Characteristics; Signal Pathway; Signal Transduction; Solid; Structure; System; Techniques; Testing; Tissues; Training; Universities; Vesicle; Work; abstracting; base; career; design; extracellular; in vitro Assay; novel; reproductive; screening; steroid hormone; tissue culture; tool; trafficking; uptake

Project Summary/Abstract Steroid hormones are a large family of molecules that play pivotal roles during childhood development. During puberty in humans, elevated secretion of gonadal steroid hormones produces secondary sex characteristics such as breast development and the appearance of facial hair. Because of such important roles of steroid hormones in maturation processes, disruption of steroid hormone signaling during childhood can cause developmental defects that last into adulthood. Understanding the machinery and regulatory mechanisms of steroid hormone signaling in normal as well as pathological conditions, therefore, contributes greatly to the promotion of healthy childhood development. The ultimate goal of this project is to elucidate as-yet-unknown machinery and regulatory mechanisms of steroid hormone release and trafficking, by using the fruitfly Drosophila as a model organism. In order to accomplish this purpose, the PI will test the hypothesis that the insect steroid hormone ecdysone is secreted from the steroidogenic tissue in a vesicle-mediated manner, challenging the conventional idea that all steroid hormones are secreted by free diffusion. During the first mentored phase of the project, the PI will work closely with his mentor, Michael O'Connor, at the University of Minnesota to develop some key in vitro methods necessary to elucidate his hypothesis. Those methods include the immunohistochemical detection of ecdysone, in vitro transporter assay and in vitro steroidogenic tissue culture. This initial step of the proposed project will help the PI master various biochemistry and cell biology techniques required to conduct the next step of the project. During the mentored phase, the PI will also undergo extensive training on teaching and scientific communication, which will be helpful in the next independent phase of his career. In the subsequent independent investigator phase, the PI will work on the regulatory mechanisms of the putative vesicle-mediated ecdysone release, by screening G protein-coupled receptors working in the steroidogenic tissue. He will also screen for a putative ecdysone importer required for its uptake by peripheral tissues. These approaches should tell us how well this novel machinery of steroid hormone secretion and trafficking is conserved among different organisms. In the long run, the PI's work has the potential to shift the paradigm of steroid hormone action and will impact a vast range of research on developmental and disease processes.

项目摘要/摘要 类固醇激素是在儿童期发育过程中起关键作用的大型分子家族。期间 人类的青春期，性腺类固醇激素的分泌升高会产生次要性特征 例如乳房发育和面部毛发的出现。由于类固醇的重要作用 成熟过程中的激素，儿童期间类固醇激素信号的破坏可能导致 发育缺陷持续到成年。了解 因此 促进健康的童年发展。该项目的最终目标是阐明尚未尚未 类固醇激素释放和贩运的机械和调节机制，使用果蝇果蝇 作为模型生物。为了实现此目的，PI将检验昆虫类固醇的假设 激素ecdysone以囊泡介导的方式从类固醇组织分泌，挑战 常规的想法是，所有类固醇激素均由游离扩散分泌。在第一个指导阶段 项目，PI将与明尼苏达大学的导师Michael O'Connor紧密合作以发展 阐明他的假设所需的一些关键体外方法。这些方法包括 ecdysone的免疫组织化学检测，体外转运蛋白测定和体外类固醇生成组织培养。 拟议项目的首要步骤将帮助PI掌握各种生物化学和细胞生物学技术 需要进行项目的下一步。在指导阶段，PI也将进行广泛 关于教学和科学交流的培训，这将在他的下一个独立阶段有所帮助 职业。在随后的独立研究者阶段，PI将致力于调节机制 假定的囊泡介导的ecdysone释放，通过筛选在该中工作的G蛋白偶联受体 类固醇组织。他还将筛选出一个假定的ecdysone进口商，以吸收外围 组织。这些方法应该告诉我们这种类固醇激素分泌的新型机械和 在不同生物体中贩运是保守的。从长远来看，PI的工作有可能改变 类固醇激素作用的范式，将影响有关发育和疾病的广泛研究 过程。