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Identification and Characterization of Novel Metabolic Regulators in Mouse and Human Liver

小鼠和人类肝脏中新型代谢调节剂的鉴定和表征

基本信息

批准号：
9762204
负责人：
Ling Yang
金额：
$ 24.38万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-15 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9762204
关键词：
1q21 AGFG1 gene Affect Autophagocytosis Autophagosome Binding Binding Proteins Bioinformatics Biological Process CREB1 gene Cancer Patient Cancerous Career Mobility Catalytic Domain Cellular biology Chinese People Cholesterol Cholesterol Homeostasis Clustered Regularly Interspaced Short Palindromic Repeats Code Confocal Microscopy Data Data Set Development Plans Diabetes Mellitus Disease Elements Epidemic Familial Combined Hyperlipidemia Fasting Fatty Liver Functional disorder Genes Genetic Transcription Glucagon Gluconeogenesis Golgi Apparatus Health Hepatic Hepatocyte Human In Vitro K22 Award Ketone Bodies Lipids Liver Liver diseases Malignant Neoplasms Measures Mediating Membrane Mentors Messenger RNA Metabolic Metabolic Diseases Metabolic Pathway Metabolic hormone Metabolism Mitochondria Mus Non-Insulin-Dependent Diabetes Mellitus Nonesterified Fatty Acids Normal tissue morphology Nutrient Obese Mice Obesity Obesity associated disease Ontology Patients Plasma Primary carcinoma of the liver cells Principal Investigator Protein Family Proteins Quantitative Reverse Transcriptase PCR RNA Regulation Research Research Personnel Research Technics Role Sampling Secure Starvation TXN gene TXNIP gene Testing Therapeutic Tissues Training Transcription Process Translational Research Triglyceride Metabolism Triglycerides Untranslated RNA Work analysis pipeline career development chromatin immunoprecipitation differential expression experience experimental study fatty acid oxidation functional genomics genome wide screen genome-wide glucose metabolism glucose-6-phosphatase in vivo insight knock-down lipid metabolism liver biopsy member new therapeutic target novel novel strategies overexpression promoter protein biomarkers skills success trafficking transcription factor transcriptome transcriptome sequencing

项目摘要

Project Summary/Abstract The long non-coding RNAs (lncRNAs) are an emerging and rapidly-growing class of functional genomic elements, and a number have been shown to regulate fundamental biological processes, but the scope of their influence in metabolic disorders remains unknown. Identifying and characterizing metabolically-relevant lncRNAs will be crucial to obtaining a better understanding the pathophysiology of obesity and other diseases of metabolism. The candidate aspires to contribute to this understanding by studying novel metabolic regulators, while developing additional experience in relevant research techniques and receiving the necessary career development training to transition to a role as an independent principal investigator. Expanding on the candidate’s recent genome-wide screen that identified 140 lncRNAs and 239 mRNAs sensitive to metabolic conditions in mouse liver, the proposed research will study the roles of one novel lncRNA, Gm15441, in regulating triglyceride (TG) and cholesterol metabolism (Aim 1) and one novel protein-coding gene, Rab30, in regulating autophagy, free fatty acid (FFA) oxidation, and TG secretion in mouse livers (Aim 2). The mechanism by which Gm15441 regulates TG and cholesterol metabolism will be defined by exploring its cis-regulation of the overlapping metabolically-relevant protein-coding gene. In preliminary experiments, knockdown of Rab30 affected autophagy and lipid metabolism in fasting mouse livers, therefore the role of Rab30 in membrane trafficking will be determined. Additionally, the comprehensive bioinformatics analysis pipeline established in the recent genome-wide screen will be applied to human liver samples, to identify novel lncRNA metabolic regulators in human liver (Aim 3). The efficacy of this pipeline for predicting the function of human genes was established in preliminary experiments by testing known metabolic genes, such as G6PC (glucose-6-phosphatase catalytic subunit), which was correctly predicted to function in gluconeogenesis. A K22 award will offer this candidate the opportunity to develop new skills in CRISPR, confocal microscopy, cell biology, and bioinformatics. The candidate will develop these skills while developing experience in pursuing research of translational significance. Gm15441, for instance, is localized in a region that is syntenic with the human 1q21-23 locus, implicated in type 2 diabetes mellitus and familial combined hyperlipidemia. The candidate has developed a comprehensive plan for the development of her career, has identified coursework that will confer necessary skills for success as an independent investigator, and has secured a team of distinguished mentors and advisors who will support her throughout her career transition. Successful completion of the work described in this proposal could provide critical insight into the regulatory networks of hepatic and systemic metabolism, and will afford the candidate the ability to achieve research independence.

项目总结/文摘