A Test of Leptin's Central Function in Zebrafish

斑马鱼瘦素中枢功能的测试

• 批准号: 8367582
• 负责人: RICHARD LYLE LONDRAVILLE
• 金额: $ 43.55万
• 依托单位: UNIVERSITY OF AKRON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-15 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8367582
• 关键词: Address; Adipose tissue; Adult; Air Sacs; Animal Model; Apoptosis; Award; Axon; Batrachoidiformes; Biological Assay; Biological Models; Biology; Caenorhabditis elegans; Candidate Disease Gene; Cardiac; Catabolism; Cell physiology; Cell surface; Code; Coupling; Development; Diabetes Mellitus; Diet; Disease; Drosophila genus; Embryo; Enrollment; Enzymes; Eye; Fishes; Funding; Genes; Genetic; Goals; Gonadal structure; Hepatic; Histology; Home environment; Hormones; Human; Human Development; Injection of therapeutic agent; Laboratories; Labyrinth; Lead; Leptin; Lipid Mobilization; Lipids; Liver; Mammals; Mentors; Metabolic; Metabolic syndrome; Methodology; Methods; Minority; Modeling; Molecular; Monitor; Morphology; Mus; Muscle; Neural Conduction; Obesity; Oligonucleotides; Physiological; Proteomics; Receptor Gene; Recombinants; Renal function; Research; Research Personnel; Research Project Grants; Resistance; Role; STEM field; Salt Gland; Scientist; Sensory; Shark; Signal Transduction; Site; Squid; Structure; Students; Testing; Tissues; Training; Transcript; Up-Regulation; Woman; Work; Zebrafish; comparative; graduate student; high school; knock-down; leptin receptor; lipid metabolism; liver function; member; notochord; programs; promoter; receptor expression; symposium; tool; undergraduate research; undergraduate student; volunteer

DESCRIPTION (provided by applicant): The overarching approach of the proposed research is to use the comparative method to understand leptin's role in the development of human diabetes and obesity. We will use the zebra fish model to test specific hypotheses about leptin function. In our last award, we established that leptin is required for normal zebra fish development, as zebra fish embryos with reduced leptin do not absorb yolk, have reduced sensory structures (eyes and inner ear), abnormal notochord, impaired cardiac function and lower metabolic rate. In this renewal proposal we will address two Specific Aims that build on our previous work: I- We will test the hypothesis that increased leptin titer activates lipid mobilization from liver in adult zebra fish. We will increase and decrease leptin titer in adult zebra fish and test for up-regulation of lipid catabolism in liver. II: We will test the hypothesisthat expression of the leptin receptor overlapping transcript (LEPROT) modulates leptin sensitivity in zebra fish. LEPROT negatively regulates cell-surface expression of the leptin receptor in humans and other mammals. Its coding sequence is contained within the leptin receptor gene via an alternate start site, and its expression is regulated by the leptin receptor promoter. In fishes, LEPROT's primary structure is conserved, but the gene is separated from the leptin receptor. We will test whether LEPROT function is conserved in fishes. The proposed research will be conducted with substantial consideration toward providing training opportunities for young scientists. Funds are requested to support graduate students and undergraduate students, and the lead investigators, graduate students, and undergraduate students will form a mentoring team for high school student volunteers. Students will be involved in hands-on research, each with their own distinct project that contributes to the overall goals of the proposal. The PI and Co-investigator have an excellent record of sponsoring undergraduate research. Independent research projects using the zebra fish model are central to their advanced undergraduate classes (e.g. Cell Physiology with an annual enrollment of 50), and the PI rewrote all introductory Biology laboratories to include undergraduate research in each laboratory. The PI also started an undergraduate research symposium in his home department (now in its 7th year) and both PI and Co-PI sponsor several Honors thesis research projects in their laboratories annually. Finally, both investigators have been successful in attracting underrepresented students into their research programs, and the PI is a member of an NSF-sponsored project dedicated to increasing representation of women and minorities in STEM disciplines (Project IDEAL). PUBLIC HEALTH RELEVANCE: The proposed studies investigate function of the hormone leptin in the zebra fish model organism. Results of these studies may lead to greater understanding of how obesity, metabolic syndrome, and diabetes develop in humans, as well as potential therapies for those diseases.

描述(由申请人提供)：建议研究的主要方法是使用比较的方法来了解瘦素在人类糖尿病和肥胖症发展中的作用。我们将使用斑马鱼模型来检验有关瘦素功能的具体假设。在我们的上一个奖项中，我们确定了瘦素是斑马鱼正常发育所必需的，因为瘦素减少的斑马鱼胚胎不能吸收卵黄，感觉结构(眼睛和内耳)减少，脊索异常，心脏功能受损和代谢率较低。在这项更新建议中，我们将解决建立在我们先前工作基础上的两个具体目标：I-我们将测试瘦素滴度增加激活成年斑马鱼肝脏脂肪动员的假设。我们将提高和降低成年斑马鱼的瘦素效价，并测试肝脏脂肪分解代谢的上调。II：我们将测试瘦素受体重叠转录本(LEPROT)的表达调节斑马鱼对瘦素敏感性的假设。LEPROT负向调节人类和其他哺乳动物细胞表面瘦素受体的表达。其编码序列通过一个交替的起始点被包含在瘦素受体基因中，其表达受瘦素受体启动子的调控。在鱼类中，LEPROT的一级结构是保守的，但该基因与瘦素受体分离。我们将测试LEPROT功能在鱼类中是否保守。拟议的研究将在为年轻科学家提供培训机会方面进行大量考虑。申请资金支持研究生和本科生，并由首席调查员、研究生和本科生组成高中生志愿者辅导团队。学生们将参与实践研究，每个人都有自己独特的项目，这些项目对提案的总体目标做出了贡献。PI和合作调查员在赞助本科生研究方面有很好的记录。使用斑马鱼模型的独立研究项目是他们高级本科课程的核心(例如，每年招生50人的细胞生理学)，PI重写了所有生物学入门实验室，将本科研究纳入每个实验室。PI还在他的家乡部门(现在是第7年)开始了一个本科生研究研讨会，PI和Co-PI每年都会在他们的实验室赞助几个荣誉论文研究项目。最后，这两位研究人员都成功地将代表性不足的学生吸引到他们的研究计划中，而PI是NSF赞助的一个项目的成员，该项目致力于增加妇女和少数族裔在STEM学科中的代表性(项目IDEAD)。 公共卫生相关性：拟议的研究调查了荷尔蒙瘦素在斑马鱼模式生物中的功能。这些研究的结果可能有助于更好地了解肥胖、代谢综合征和糖尿病在人类中的发展过程，以及这些疾病的潜在治疗方法。

项目成果

Leptin-a mediates transcription of genes that participate in central endocrine and phosphatidylinositol signaling pathways in 72-hour embryonic zebrafish (Danio rerio).

瘦素-a 介导参与 72 小时胚胎斑马鱼 (Danio rerio) 中枢内分泌和磷脂酰肌醇信号通路的基因转录。

• DOI: 10.7717/peerj.6848
• 发表时间: 2019
• 期刊: PeerJ
• 影响因子: 2.7
• 作者: Tuttle,Matthew;Dalman,MarkR;Liu,Qin;Londraville,RichardL
• 通讯作者: Londraville,RichardL

Leptin and leptin receptor: analysis of a structure to function relationship in interaction and evolution from humans to fish.

• DOI: 10.1016/j.peptides.2012.10.002
• 发表时间: 2012-12
• 期刊: Peptides
• 影响因子: 3
• 作者: Prokop JW;Duff RJ;Ball HC;Copeland DL;Londraville RL
• 通讯作者: Londraville RL

Beyond thermoregulation: metabolic function of cetacean blubber in migrating bowhead and beluga whales.

• DOI: 10.1007/s00360-016-1029-6
• 发表时间: 2017-01
• 期刊: Journal of comparative physiology. B, Biochemical, systemic, and environmental physiology
• 作者: Ball HC;Londraville RL;Prokop JW;George JC;Suydam RS;Vinyard C;Thewissen JG;Duff RJ
• 通讯作者: Duff RJ

On the Molecular Evolution of Leptin, Leptin Receptor, and Endospanin.

• DOI: 10.3389/fendo.2017.00058
• 发表时间: 2017
• 期刊: Frontiers in endocrinology
• 影响因子: 5.2
• 作者: Londraville RL;Prokop JW;Duff RJ;Liu Q;Tuttle M
• 通讯作者: Tuttle M

Leptin in teleost fishes: an argument for comparative study.

• DOI: 10.3389/fphys.2011.00026
• 发表时间: 2011
• 期刊: Frontiers in physiology
• 影响因子: 4
• 作者: Copeland DL;Duff RJ;Liu Q;Prokop J;Londraville RL
• 通讯作者: Londraville RL