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: 8514670
• 负责人: Naoki Yamanaka
• 金额: $ 9.05万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-20 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8514670
• 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; Principal Investigator; 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; base; career; design; extracellular; in vitro Assay; novel; reproductive; screening; steroid hormone; tissue culture; tool; trafficking; uptake

DESCRIPTION (provided by applicant): 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 Principal Investigator 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 Principal Investigator 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 Principal Investigator master various biochemistry and cell biology techniques required to conduct the next step of the project. During the mentored phase, the Principal Investigator 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 Principal Investigator 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 Principal Investigator'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.

描述（由申请人提供）：类固醇激素是一个大家族的分子，在儿童发育过程中发挥着关键作用。在人类青春期，性腺类固醇激素分泌增加会产生第二性征，例如乳房发育和面部毛发的出现。由于类固醇激素在成熟过程中发挥着如此重要的作用，童年时期类固醇激素信号传导的破坏可能会导致发育缺陷，并持续到成年。因此，了解正常和病理条件下类固醇激素信号传导的机制和调节机制，对于促进健康的儿童发育做出了巨大贡献。该项目的最终目标是通过使用果蝇作为模式生物来阐明类固醇激素释放和运输的未知机制和调节机制。为了实现这一目的，首席研究员将检验昆虫类固醇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的假设，挑战所有类固醇激素都是通过自由扩散分泌的传统观点。在该项目的第一个指导阶段，首席研究员将与明尼苏达大学的导师迈克尔·奥康纳密切合作，开发一些必要的关键体外方法来阐明他的假设。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生成组织培养。拟议项目的第一步将帮助首席研究员掌握进行项目下一步所需的各种生物化学和细胞生物学技术。在指导阶段，首席研究员还将接受广泛的教学和科学交流培训，这将有助于他职业生涯的下一个独立阶段。在随后的独立研究者阶段，首席研究员将通过筛选在类固醇生成组织中起作用的 G 蛋白偶联受体，研究假定的囊泡介导的蜕皮激素释放的调节机制。他还将筛选外周组织吸收所需的假定的蜕皮激素输入者。这些方法应该告诉我们这种类固醇激素分泌和运输的新机制在不同生物体中的保守程度如何。从长远来看，首席研究员的工作有可能改变类固醇激素作用的范式，并将影响发育和疾病过程的广泛研究。