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: 8351891
• 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 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8351891
• 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; Screening procedure; 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; 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. PUBLIC HEALTH RELEVANCE: Steroid hormones regulate multiple physiological processes and are involved in many types of developmental diseases and cancers. This project is designed to answer the question of how steroid hormone release and uptake are regulated at the molecular level. The expected outcome of this project will shift the paradigm of steroid hormone biology and thus will facilitate development of new strategies for disease treatment and human health improvement.

描述（由申请人提供）：类固醇激素是在儿童发育过程中起关键作用的大型分子。在人类青春期期间，性腺类固醇激素的分泌升高会产生诸如乳房发育和面部头发的出现之类的继发性特征。由于类固醇激素在成熟过程中的如此重要的作用，儿童期间类固醇激素信号的破坏会导致持续到成年的发育缺陷。因此，了解正常和病理状况下类固醇激素信号传导的机制和调节机制，因此有助于促进健康的儿童发展。该项目的最终目的是通过将果蝇果蝇作为模型有机体阐明类固醇激素释放和运输的尚未尚未尚未的机制。为了实现这一目的，主要研究者将检验以下假设：昆虫类固醇激素codysone以囊泡介导的方式从类固醇组织中分泌，这挑战了所有类固醇激素均由自由扩散分泌的常规观念。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（Michael O'Connor）紧密合作，以开发一些阐明他的假设所需的重要体外方法。这些方法包括ecdysone，体外转运蛋白测定和体外类固醇生成组织培养的免疫组织化学检测。拟议项目的这一第一步将有助于主要研究人员掌握进行下一步的各种生物化学和细胞生物学技术。在指导阶段，首席研究人员还将接受有关教学和科学交流的广泛培训，这将在他职业生涯的下一个独立阶段有所帮助。在随后的独立研究者阶段，主要研究者将通过筛选在类固醇组织中工作的G蛋白偶联受体来处理推定囊泡介导的ecdysone释放的调节机制。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和贩运的新型机制在不同生物体中得到了保存。从长远来看，主要研究者的工作有可能改变类固醇激素作用的范式，并会影响有关发育和疾病过程的大量研究。 公共卫生相关性：类固醇激素调节多种生理过程，并参与了许多类型的发育疾病和癌症。该项目旨在回答类固醇激素释放和摄取如何在分子水平调节的问题。该项目的预期结果将改变类固醇激素生物学的范式，因此将促进发展新的疾病治疗和人类健康策略。