loading
loading
NIH grant 1R01DK145985-01A1: Unveiling skin-derived SIRT1 as a therapeutic target for diabetic neuropathy
Institute: {'code': 'DK', 'abbreviation': 'NIDDK', 'name': 'National Institute of Diabetes and Digestive and Kidney Diseases', 'admin_org_id': '12500020', 'admin_funding_url': ''}. PI: Cheng-Ying Ho. Award: $723956.
Start: 2026-08-28T00:00:00.
PROJECT SUMMARY
Diabetic neuropathy (DN) is a prevalent and debilitating complication of diabetes characterized by intense pain
and lack of effective treatments. A major obstacle to therapeutic advancement is the limited understanding of
its pathophysiological mechanisms and actionable drug targets. Our recent study reveals a pivotal role of skin
keratinocyte-derived sirtuin 1 (SIRT1), an NAD+-dependent deacetylase, in the pathogenesis of DN. We
discovered that reduced SIRT1 deacetylase activity in diabetic skin decreases brain-derived neurotrophic
factor (BDNF) expression and causes loss of Meissner corpuscles and degeneration of their A afferents,
which culminate in the symptoms of DN. Encouragingly, overexpression of skin-derived SIRT1 reversed
neuropathy in DN mouse models, highlighting its potential as a therapeutic target. Moreover, oral
supplementation with the SIRT1 activator nicotinamide riboside (NR) showed modest improvements in DN
mouse models, further validating the therapeutic promise of targeting SIRT1. However, the limited efficacy of
oral NR underscores the need for innovative delivery strategies. Developing topical formulations of NR may
enable localized treatment, enhancing efficacy and reducing dosage requirements. Further research into
topical delivery methods is crucial to optimize therapeutic outcomes and improve the quality of life for DN
patients.
Our long-term goal is to elucidate the pathophysiological mechanisms underlying DN and leverage the
knowledge to develop effective treatments. The current project objective is to characterize how skin-derived
SIRT1 deficiency contributes to degeneration and impaired regeneration of peripheral sensory axons and
explore innovative therapeutic strategies to correct the deficiency. Our central hypothesis is that retrograde
degeneration and impaired regeneration of peripheral sensory axons, driven by skin-derived SIRT1 deficiency,
are central to DN pathology and can be reversed through topical NR supplementation. The hypothesis will be
tested via the following specific aims: (1) Investigate the protective role of skin-derived SIRT1 in peripheral
sensory axons; (2) Define the mechanism of peripheral sensory axon regeneration facilitated by skin-derived
SIRT1; (3) Evaluate the efficacy of topical NR for reversing DN.
At the successful completion of this work, we will uncover novel therapeutic targets and develop practical
interventions for diabetic neuropathy. Achieving these objectives would mark a significant step toward
improving the lives of millions affected by DN, a challenging condition that currently lacks cure. This aligns with
the NIDDK mission of alleviating and conquering DN, a common complication of diabetes.document fetched 2026-09-06 02:47