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Dissecting Sex-Specific Metabolic Responses to Inflammation

剖析性别特异性对炎症的代谢反应

基本信息

批准号：
10596168
负责人：
Joni Nikkanen
金额：
$ 9万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
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：
2022-04-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10596168
关键词：
Accounting Affect Award BCL6 gene Basal metabolic rate Binding Sites Biological Assay CRISPR/Cas technology Caring ChIP-seq Communicable Diseases Data Data Set Escherichia coli Infections Exhibits Fatty Liver Fatty acid glycerol esters Female Genes Genetic Transcription Genomics Goals Gonadal Steroid Hormones Hepatic High Fat Diet Holly Host Defense Mechanism Housing Human Hyperlipidemia Infection Inflammation Institution Laboratory Research Life Lipase Lipids Lipoproteins Liver Masks Mediating Mentors Mentorship Metabolic Metabolic Diseases Metabolism Modeling Molecular Mus Obesity Outcome Overnutrition Pathogenicity Pathway interactions Phase Phenotype Plasma Postdoctoral Fellow Predisposing Factor Predisposition Regulation Research Research Personnel Risk Factors Role Sampling Scintillation Counting Sepsis Sex Bias Sex Differences Survival Rate System Temperature Testing Tracer Training Triglycerides United States United States National Institutes of Health Very low density lipoprotein Viral alternative treatment candidate identification career feeding fitness gallin genetic manipulation human model improved insight knock-down lipid metabolism liver function liver metabolism male men mortality mouse model non-alcoholic fatty liver disease novel novel strategies overexpression particle pathogen pharmacologic post-doctoral training programs promoter response sex sexual dimorphism skills steroid metabolism thermal stress transcription factor transcriptome sequencing treatment strategy

项目摘要

Project Summary Sex is a major factor affecting survival from life-threatening infections, but current treatment alternatives do not provide sex-specific care. To discover novel strategies to treat severe infections, I wish to unravel sex-specific mechanisms of the liver that improve host fitness during infections. My central hypothesize is that sex-specific factors of the liver impact the survival of infected mice, and I wish to target these factors to improve survival rates. During my postdoctoral training, I have developed mouse models that replicate human responses to infections and found that housing infected mice at their thermoneutral temperature better mirrors infected humans than housing mice at ambient room temperature. My recent studies demonstrate that housing infected mice at thermoneutrality compromises the survival of female mice as compared to males, and this is due to a dramatic accumulation of plasma triglycerides. My further data demonstrate that this is regulated by a hepatic transcription factor, BCL6, which targets hepatic lipoprotein metabolism to mediate its critical function in systemic lipid handling. In my K99 Aim1, I will start testing candidate factors that function downstream of BCL6 and are novel regulators of host fitness during pathogenic infections. I will continue studying systemic lipid handling following infection in my K99 Aim 2 and perform VLDL synthesis and clearance assays to understand the mechanism of infection-induced hyperlipidemia in mice. After the K99 training phase, I wish to establish an independent research laboratory in one of the major institutions in the United States to study sex-specific metabolic adaptations in the liver that impact the outcome of infections. I aim to expand this question during the independent R00 phase and identify hepatic factors that predispose men to NAFLD. My exciting new studies suggest that while hepatic BCL6 protects males during infection, the opposite occurs when male mice are fed with high-fat diet. There, hepatic BCL6 predisposes males to fatty liver and hepatic steatosis. In my R00 Aim, I wish to study this as an independent investigator, but I need further training in sex steroid metabolism and hepatic gene manipulation before independence. The NIH Pathway to Independence Award will allow me the two years of critical training to develop these skills in Dr. Holly Ingraham’s lab. In her lab, I will develop the skills needed for my independent career, and her passion in mentorship will be invaluable for my training before establishing my independent research group.

项目总结