Evaluating the renal complications in cockayne syndrome

The National Institute of Diabetes and Digestive and Kidney Diseases, part of the Department of Health and Human Services National Institutes of Health, awarded Mercer University $178,400 on August 1, 2026, under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847) to evaluate renal complications in Cockayne syndrome.

The research will identify the molecular basis of kidney dysfunction in Cockayne syndrome, a multi-system premature-aging disorder caused by DNA repair gene mutations, and develop novel therapeutic strategies targeting NAD metabolism. Cockayne syndrome patients exhibit shortened life expectancy, neurodegeneration, vision and hearing impairments, and kidney abnormalities; kidney dysfunction is a significant cause of mortality in this population. The study will pursue two specific aims: defining cellular and molecular mechanisms of kidney injury in Cockayne syndrome, including mitochondrial dysfunction and cell death pathways across nephron compartments through in vivo phenotyping of Cockayne syndrome mouse kidneys and in vitro studies in renal cells; and investigating transcriptional and epigenetic regulation of NAD metabolic genes while evaluating the therapeutic potential of NAD replenishment. The research builds on preliminary findings demonstrating that kidney damage in Cockayne syndrome is driven by transcriptional repression of QPRT, a rate-limiting enzyme in NAD biosynthesis, resulting in NAD depletion, mitochondrial dysfunction, and tubular cell death.

The award runs from August 1, 2026, through June 30, 2030, with place of performance in Savannah, Georgia.

Abstract

Cockayne syndrome (CS) is a multi-system disorder characterized by premature aging, resulting from MU- tations in genes essential for DNA repair. Patients with CS exhibit various symptoms, including significantly shortened life expectancy, short stature, microcephaly, neurodegeneration, photosensitivity, vision and hearing impairments, as well as abnormalities in bones and kidneys. A notable molecular feature in cells derived from CS patients is the depletion of intracellular nicotinamide adenine dinucleotide (NAD+), a critical molecule for maintaining cellular health, stress response, and particularly renal function. Despite kidney dysfunction being a significant cause of mortality in CS patients, the molecular mechanisms underlying this dysfunction, particularly the connection between NAD+ depletion and renal issues, remain unclear. The objective of this R16 grant proposal is to uncover the molecular basis of kidney dysfunction in CS and identify novel therapeutic strategies targeting NAD⁺ metabolism. Our recent findings demonstrate that KID- NEY damage in CS is driven by transcriptional repression of qprt, a rate-limiting enzyme in the DE novo NAD⁺ biosynthesis pathway, through stabilization of the transcriptional repressor ATF3. This repression results in NAD⁺ depletion, mitochondrial dysfunction, and tubular cell death. These insights suggest that NAD⁺ metabolism is a modifiable driver of renal injury in CS. This study will pursue two specific aims: (1) to define the cellular and molecular mechanisms of kidney injury in CS, including mitochondrial dysfunction and cell death pathways across nephron compartments, and (2) to investigate the transcriptional and EPI- genetic regulation of NAD⁺ metabolic genes and evaluate the therapeutic potential of NAD⁺ replenishment. Aim 1 combines in vivo phenotyping of CS mouse kidneys and in vitro studies in CSA/B-deficient renal cells to elucidate compartment-specific injury mechanisms. Aim 2 utilizes RNA-SEQ, chip-SEQ, and functional rescue experiments using inducible qprt expression and NAD⁺ supplementation to define regulatory net- works and therapeutic reversibility. This research is innovative in its shift from viewing NAD⁺ depletion as a consequence of DNA damage to understanding IT as a transcriptionally regulated event that drives organ failure. By integrating molecular profiling with functional interventions, this work may uncover new para- digms for NAD⁺-related diseases and lead to precision strategies for kidney protection in CS and other aging-associated disorders. This project is expected to have a positive impact not only on a better under- standing of the biology of premature aging and its impact on prevention, but also on developing effective interventions to maintain health, well-being, and function and prevent or reduce the burden of age-related diseases. We are confident that our substantial expertise and experience in both CS and NAD+ intervention research provide a strong foundation for effectively testing the hypotheses set forth in this project.