Location: Children's Nutrition Research Center
Project Number: 3092-10700-069-003-S
Project Type: Non-Assistance Cooperative Agreement
Start Date: Apr 1, 2024
End Date: Mar 31, 2029
Objective:
Objective 1: Investigate the role of SIRT2 in the regulation of Akt and insulin signaling.
Objective 2: Develop robust deep learning models and computational tools to infer alternative polyadenylation and alternative splicing from bulk RNA-seq data.
Objective 3: Decode nutrition-dependent mRNA processing in cancer by integrated analysis of public datasets from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA).
Objective 4: Perform an unbiased screen for CoRSIVs in African Americans and test for associations between CoRSIV methylation at birth and later obesity.
Objective 5: Perform the first ever unbiased screen for mouse metastable epialleles and test for associations between methylation at these loci and adult body weight.
Approach:
Insulin regulates fundamental aspects of metabolism and aging. Caloric restriction delays aging and enhances insulin sensitivity. Caloric restriction increases SIRT2 expression, and we have evidence that, in muscle, SIRT2 enhances Akt-mediated insulin signaling. We will investigate the mechanisms of SIRT2 and Akt’s membrane translocation. We have also generated novel transgenic mice with skeletal muscle-specific expression of SIRT2, and will use them study SIRT2’s action on insulin signaling. Cancer is one of the leading causes of illness and death worldwide. Overweight and obesity increase the risk of certain types of cancer, as does a diet high in processed foods and unhealthy fats. However, the molecular mechanisms driving these associations remain unclear. Variation in RNA processing, including alternative polyadenylation and alternative splicing, is influenced by nutrition, and associated with cancer risk. However, the role of nutrient-induced mRNA processing in cancer is uncharted. We aim to decode and investigate diet-induced RNA processing and the underlying molecular mechanisms to guide nutrition interventions for cancer prevention. Metabolic programming occurs when nutrition affects development, causing structural or functional changes that influence later health. Nutrition affects developmental epigenetics, particularly DNA methylation, making it a prime mechanism for metabolic programming. We pioneered the identification of human genomic regions of systemic interindividual epigenetic variation (CoRSIVs) to accelerate progress in this area. We will identify CoRSIVs in African Americans and determine if CoRSIV methylation in African American newborns predicts childhood obesity. We will also identify mouse metastable epialleles (a subclass of CoRSIVs) and test associations between methylation at these loci and later obesity. A better understanding of how nutrition affects these various molecular mechanisms should eventually lead to the development of nutritional interventions to improve human health.
