Location: Children's Nutrition Research Center
Project Number: 3092-10700-069-000-D
Project Type: In-House Appropriated
Start Date: Mar 4, 2024
End Date: Mar 3, 2029
Objective:
Obesity and its associated metabolic disorders represent a serious health problem to our society. To address this researchers aim to: 1) define the role of hepatocyte reduced folate transporter, SLC19A1, in the progression of non-alcoholic fatty liver diseases; 2) determine the role of phenylalanine metabolism of both the host and microbiome in non-alcoholic fatty liver diseases development; 3) determine whether the lateral habenula to serotonin circuit inhibits food intake; 4) determine the physiological roles of genetically defined parabrachial nucleus-originated neural circuit in differential control of feeding behavior and energy metabolism; 5) determine whether cholinergic basal forebrain circuits differentially respond to appetitive and aversive stimuli to drive feeding and food avoidance behaviors; 6) determine the role of brain AMPK in glycemic control during overnutrition; 7) determine the impact of digenic heterozygous ciliary gene loss on ciliary structure, function, and weight regulation; 8) investigate the role of SIRT2 in the regulation of Akt and insulin signaling; 9) develop robust deep learning models and computational tools to infer alternative polyadenylation and alternative splicing from bulk RNA-seq data; 10) decode nutrition-dependent mRNA processing in cancer by integrated analysis of public datasets from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA); 11) perform an unbiased screen for CoRSIVs in African Americans and test for associations between CoRSIV methylation at birth and later obesity; and 12) perform the first ever unbiased screen for mouse metastable epialleles and test for associations between methylation at these loci and adult body weight.
Approach:
A multi-discipline approach will be undertaken to address these concerns. We will test our hypothesis that SLC19A1 in hepatocytes and folate deficiency will exacerbate non-alcoholic fatty liver disease (NAFLD) in the context of diet-induced obesity and we will test that nutritional availability of phenylalanine alters the gut microbiota to affect host metabolism and susceptibility to NAFLD. Researchers will continue to unravel the complex synaptic connectivity, modes of neurotransmission, and/or plasticity within these neurocircuits for feeding regulation. Since AMPK is activated by metformin and is considered to mediate at least some of the effects of metformin, scientists will test that AMPK in the brain responds to metformin as well as to distinct nutritional conditions to control whole-body glucose metabolism. Researchers will test that digenic heterozygous loss of ciliary genes causes a fundamental defect in ciliary function and results in obesity. Scientists will decode and investigate diet-induced RNA processing and the underlying molecular mechanisms to guide nutrition interventions for cancer prevention. Researchers will identify CoRSIVs in African Americans and determine if CoRSIV methylation in African American newborns predicts childhood obesity.
