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.

项目概要/摘要 类固醇激素是一个大分子家族，在儿童发育过程中发挥着关键作用。期间 人类青春期，性腺类固醇激素分泌增加，产生第二性征 例如乳房发育和面部毛发的出现。由于类固醇的如此重要作用 成熟过程中的激素，童年时期类固醇激素信号的破坏可能会导致 持续到成年的发育缺陷。了解机制和监管机制 因此，正常和病理条件下的类固醇激素信号传导对 促进儿童健康发展。该项目的最终目标是阐明目前未知的 利用果蝇研究类固醇激素释放和运输的机制和调节机制 作为模式生物。为了实现这一目的，PI 将测试昆虫类固醇的假设 激素蜕皮激素以囊泡介导的方式从类固醇生成组织中分泌，挑战 传统观点认为所有类固醇激素都是通过自由扩散分泌的。在第一个指导阶段 项目负责人将与他在明尼苏达大学的导师 Michael O'Connor 密切合作，开发 阐明他的假设所必需的一些关键体外方法。这些方法包括 蜕皮激素的免疫组织化学检测、体外转运蛋白测定和体外类固醇组织培养。 拟议项目的第一步将帮助 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 还将经历广泛的 教学和科学传播方面的培训，这将有助于他的下一个独立阶段 职业。在随后的独立调查阶段，PI将致力于研究监管机制 通过筛选 G 蛋白偶联受体，推测囊泡介导的蜕皮激素释放 类固醇生成组织。他还将筛选外周组织吸收所需的假定的蜕皮激素进口商 组织。这些方法应该告诉我们这种新的类固醇激素分泌机制和 贩运在不同的生物体之间是保守的。从长远来看，PI 的工作有可能改变 类固醇激素作用的范例，并将影响发育和疾病的广泛研究 流程。