Nicotinamide adenine dinucleotide (NAD+) is an essential cofactor involved in various cellular biochemical reactions and contributes to the regulation of Ca2+ signaling, chromatin structure, DNA repair and lifespan. To date, how eukaryote cells transport and utilize NAD+ precursors as well as the signaling pathways that regulate NAD+ homeostasis remain unclear. Studying NAD+ homeostasis is also complicated by the complex and dynamic flexibility of precursors cells use to generate NAD+. Nicotinamide riboside (NR) and nicotinamide (NAM) are key pyridine metabolites that play important roles in maintaining NAD+ pools as well as calorie restriction (CR)-induced lifespan. To further understand the mechanisms of NAD+ homeostasis, we have established NR-specific and NAM-specific reporter genetic screen systems and identified yeast mutants with altered NAD+ metabolism. Our studies suggest that phosphate responsive PHO signaling and glucose signaling pathways contribute to controlling the NR branch of NAD+ metabolism. We have recently identified additional novel NAD+ homeostasis factors in the NAM branch. The current proposal builds on our recent studies of these factors and the interplay between components in NR/NAM/NAD+ metabolism and longevity-related nutrient signaling pathways. The long-term goal is to understand the mechanisms by which cells maintain NAD+ homeostasis in response to changes in growth conditions. The major hypothesis is that NAD+ homeostasis is modulated by nutrient-sensing signaling pathways, which play important roles in determining cell fitness and survival. Intracellular compartmentalization of NAD+ intermediates and homeostasis factors also contribute to the complex interplay of NAD+ homeostasis factors and nutrient sensing pathways.
The specific aims of the projects are:
Aim 1) To study how NAD+ precursor assimilation factors regulate NAD+ homeostasis, Aim 2) To study the cross-regulation of NAD+ homeostasis and nutrient sensing pathways, and Aim 3) To Identify and study novel NAD+ homeostasis factors in the NA/NAM salvage pathway. To achieve theses goals we will employ a combination of molecular genetics and biochemical methods to analyze genes, proteins and pathways involved. These studies will increase our understanding of how eukaryotic cells regulate NAD+ homeostasis in response to changes in growth conditions, and which longevity-related nutrient sensing signaling pathways are involved. Overall Significance: Our findings will contribute to the understanding of the molecular basis of the complex regulation of NAD+ homeostasis and cell life span as well as metabolic disorders related to aberrant NAD+ metabolism in human.

Public Health Relevance

Relevance to public health: Niacin (vitamin B3, a NAD+ precursor) is widely used as a food supplement to improve heath. Administration of NAD+ precursors has also been shown to ameliorate human deficiencies related to aberrant NAD+ metabolism. This research utilizes the genetically amenable model system, budding yeast, to study the regulation of NAD+ homeostasis and signaling. Many components in NAD+ biosynthesis and metabolic pathways are conserved from yeast to mammals. Therefore, our findings are likely to provide insight into the development of therapeutic reagents for NAD+ deficiency-associated diseases such as diabetes and cancers, and also have broad implications for improving human nutrition and health.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Cellular Mechanisms in Aging and Development Study Section (CMAD)
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Maas, Stefan
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University of California Davis
Schools of Medicine
United States
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