Nicotinamide adenine dinucleotide (NAD) is a redox cofactor required by enzymes essential to energy production and numerous other cellular processes. NAD also serves as a co-substrate for several classes of signaling enzymes, each of which cleaves the molecule to release nicotinamide. Cellular NAD is derived from dietary tryptophan (de novo synthesis), nicotinic acid (the Preiss-Handler pathway) or recycled from nicotinamide via the NAD salvage pathway. NAD deficiency can be triggered by a variety of cellular stresses, including DNA damage, and is thought to contribute to pathophysiology in a number of metabolic, neurological, and muscular diseases: conversely, increasing NAD+ has been suggested as a promising therapeutic strategy. Here, researchers will collaborate to develop and utilize a cellular High Throughput Screening (HTS) assay to discover and validate small molecules that increase intracellular NAD+ levels. These studies should identify novel small molecules with great therapeutic potential for a myriad of neurological and muscular including brain ischemia, Wallerian nerve degeneration, misfolded prion protein toxicity, Alzheimer's disease (AD), mitochondrial myopathy (MM), age related sarcopenia and Duchenne's muscular dystrophy(DMD).

Public Health Relevance

Deficiency in the levels of oxidized Nicotinamide adenine dinucleotide (i.e. NAD+) is noted in a number of neurological, muscular and metabolic diseases. Conversely, increasing NAD+ has been suggested as a promising therapeutic strategy for these disorders. Here researchers will collaborate to develop a cellular HTS assay to identify and validate small molecules that increase intracellular NAD+ levels as potential therapeutic strategies for a variety of neurological and muscular diseases including disorders including brain ischemia, Wallerian nerve degeneration, misfolded prion protein toxicity, Alzheimer's disease (AD), mitochondrial myopathy (MM), age related sarcopenia and Duchenne's muscular dystrophy(DMD).

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Project #
1R61NS111375-01A1
Application #
9955638
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Nuckolls, Glen H
Project Start
2020-06-15
Project End
2021-05-31
Budget Start
2020-06-15
Budget End
2021-05-31
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Physiology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104