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Alternative polyadenylation as a genetic regulatory mechanism to bridge genome to phenome in the nervous system

替代多腺苷酸化作为连接神经系统基因组和表型的遗传调控机制

基本信息

批准号：
10541679
负责人：
Julianna Nicole Brutman
金额：
$ 3.68万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10541679
关键词：
Anorexia Anorexia Nervosa Appetite Alteration Appetite Disorder Appetite Regulation Appetitive Behavior Behavioral Bioinformatics Biology Body Weight Cancer Patient Cannabis sativa plant Cell Culture Techniques Cells Clustered Regularly Interspaced Short Palindromic Repeats Complex Computer Models Data Dependovirus Desire for food Development Diabetes Mellitus Disease Eating Eating Disorders Ensure Exhibits Exposure to Feeding Patterns Feeding behaviors Food Genes Genetic Genome Goals Health Heart Diseases Hyperphagia Hypothalamic structure Institution Investigation Knock-out Knockout Mice Knowledge Lead Learning Link Malignant Neoplasms Maps Mediating Mental disorders Messenger RNA Metabolic Molds Molecular Mus Nervous system structure Neuraxis Neurobiology Neurons Neurosciences Neurosciences Research Nuclear Export Obesity Operative Surgical Procedures Palate Pathologic Pathway interactions Pattern Peptide Hydrolases Pharmaceutical Preparations Phase Phenotype Polyadenylation Positioning Attribute Process Protein Array Proteins Proteomics Psychopathology Publishing RNA RNA Processing RNA Splicing RNA Stability Rattus Regulation Research Research Institute Research Personnel Research Project Grants Research Training Rodent Site Structure of nucleus infundibularis hypothalami Synaptic plasticity Testing Tissue Inhibitor of Metalloproteinases Tissue-Specific Gene Expression Training Training Support Transcript United States Universities Washington Weight Gain Work base behavior influence behavioral phenotyping cancer cachexia career comorbidity design design verification diet-induced obesity energy balance experimental study feeding gene product innovation mRNA Expression metabolic phenotype meter mortality mouse model multiple omics neurogenetics novel obesity development overweight adults phenome pre-doctoral professor protein expression single cell sequencing skills small hairpin RNA synaptic function targeted treatment vector

项目摘要

PROJECT SUMMARY Anorexia nervosa is the deadliest psychological disorder with an estimated 10% lifetime disease mortality rate, while over 1/3 of all cancer patients will die from disease-based anorexia, not the cancer itself. On the opposite end of the spectrum, over 2/3 of US adults are overweight or obese, and this number, as well as the rates of associated comorbidities such as heart disease, diabetes, and cancer, is only expected to increase in the coming years. Despite the opposite directionality of these eating disorders, dysfunctional eating in obesity and anorexia is mediated by common appetite circuitry in the central nervous system (CNS). Numerous studies have documented a coordinated and complex pattern of changes in multiple gene products in these appetite centers following periods of excessive or inadequate eating. These observations strongly suggest that the behavioral decision to eat excessively or inadequately is likely driven by a multitargeted, maladaptive genetic reprogramming process in CNS appetite centers. Thus, a core question is what global process could coordinate such changes in multiple gene products? My published studies have demonstrated that appetite changes align with changes in alternative polyadenylation (APA) in the hypothalamus. APA is a rapid, activity-dependent RNA processing mechanism that regulates mRNA transcript stability, maturation, and localization. I identified a significant APA pattern change on tissue inhibitor of metalloproteinases 2 (Timp2), a gene previously implicated in the development of an obese phenotype. Thus, I am exploring the hypothesis that Timp2 APA in the arcuate nucleus (ARC) of the hypothalamus meters the development of obesity. My proposed experiments in the F99 phase will show that 1) Timp2 mRNA is necessary for appetite control in the ARC, and that 2) APA regulation of ARC Timp2 is necessary to counteract hyperphagia and obesity. These studies will be the first to functionally link APA regulation to feeding behavior and will serve as the basis of further genome to behavioral phenome studies in my independent career. My Sponsor, Dr. Gary Wayman, and Co-Sponsors, Drs. Suzanne Appleyard and Emily Qualls-Creekmore, are established neuroscientists at Washington State University with expertise in molecular neuroscience (Wayman) and ingestive behavior (Appleyard and Qualls-Creekmore). My proposed Research and Training plan will strengthen my theoretical and technical understanding of neurogenetics. In the pre-doctoral F99 phase, I will learn shRNA and CRISPR/SaCas9 vector design and validation strategies, cell culture techniques, stereotaxic surgeries, and advanced metabolic analyses. In the postdoctoral K00 phase, I will build upon these skills and learn to use genetic mouse models, multi-omics, advanced bioinformatics, and AI computational models to map genome to phenome regulation. Overall, the proposed training will optimally position me to start an independent research career at a leading neuroscience research institute and advance our understanding of RNA regulation as a functional link between the genome and the behavioral phenome.

项目总结