# Understanding the Regulation of NAD+ Homeostasis and Signaling

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2022 · $377,070

## Abstract

Project Summary
Nicotinamide adenine dinucleotide (NAD+) is an essential metabolite involved in various cellular processes.
NAD+ metabolism is also an emerging therapeutic target for several human diseases. The NAD+ pool is
maintained by three biosynthesis pathways, which are largely conserved from bacteria to human. The
regulation of NAD+ metabolism is incompletely understood due to the dynamic flexibility of NAD+ intermediates,
the redundancy of biosynthesis pathways, and the complex interconnections among them. The major goal of
this proposal is to uncover novel signaling factors that regulate NAD+ homeostasis and to study the underlying
mechanisms. Our studies utilize the genetically tractable budding yeast Saccharomyces cerevisiae that has
consistently served as an efficient model system to study cellular mechanisms broadly conserved among
eukaryotes. We have recently established an NAD+ intermediate-specific genetic system to identify factors that
regulate each branch of the NAD+ biosynthesis pathways. Our studies have uncovered novel NAD+
homeostasis factors including transcription factors, NAD+ intermediates transporters, and nutrient-sensing
signaling pathways. The current proposal builds on our recent studies of these factors and the interplay
between components in NAD+ metabolism and longevity-related nutrient signaling pathways. Our studies in
Project 1 and Project 2 will address specific hypotheses derived from our recent studies to elucidate the
mechanisms of regulation. A few major gaps in our knowledge of the mechanisms regulating NAD+
homeostasis will be addressed: 1) Which and how signaling pathways regulate NAD+ homeostasis? 2) Which
and how cellular processes contribute to the turnover of NAD+ and its intermediates? 3) What is the molecular
basis for the cross-regulation of NAD+ biosynthesis and nutrient-sensing pathways? The long-term goal is to
understand how cells maintain NAD+ homeostasis in response to changes in growth conditions. The major
hypothesis is that NAD+ homeostasis is co-regulated by nutrient-sensing signaling pathways. Intracellular
compartmentalization of NAD+ intermediates and homeostasis factors also contribute to the complex interplay
of NAD+ homeostasis factors and nutrient sensing pathways. 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: NAD+ preservation helps ameliorate age-associated metabolic disorders. Our
findings will contribute to understanding the molecular basis and regulation of NAD+ homeostasis as well as the
mechanisms underlying metabolic disorders related to aberrant NAD+ metabolism in human.

## Key facts

- **NIH application ID:** 10433915
- **Project number:** 5R35GM141855-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Su-Ju Lin
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $377,070
- **Award type:** 5
- **Project period:** 2021-06-17 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10433915

## Citation

> US National Institutes of Health, RePORTER application 10433915, Understanding the Regulation of NAD+ Homeostasis and Signaling (5R35GM141855-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10433915. Licensed CC0.

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