Peripheral neuropathy is the most common complication of diabetes and will afflict over half of the 25 million Americans who currently suffe from diabetes. There is no FDA-approved therapy to prevent neuropathy or reverse the distal degenerative neuropathy already present in many newly diagnosed diabetic patients. Recent clinical and experimental studies have emphasized that retraction of the peripheral terminals of small sensory axons as an early feature of diabetic neuropathy. This offers a window of opportunity to halt or reverse the dying-back of peripheral terminals before neuronal death. We have recently discovered that muscarinic M1 receptor antagonists can enhance axonal outgrowth from adult rat sensory neurons grown under defined in vitro conditions and also prevent distal neuropathy in diabetic rodents. This prompts us to propose that adult peripheral neurons are under constant cholinergic constraint that moderates the growth capacity of axon terminals and that manipulating this endogenous system offers a novel therapeutic approach to reversing early diabetic neuropathy. We will investigate the mechanism of cholinergic constraint in adult sensory neurons and determine whether diabetes alters this process as part of the pathogenic mechanism of diabetic neuropathy. We will also demonstrate the therapeutic potential of manipulating this endogenous cholinergic constraint mechanism to reverse established distal neuropathy in diabetic rodents and use corneal confocal microscopy to illustrate that preclinical efficacy of a therapeutic can be rapidly translated to demonstrable efficacy in diabetic subjects with peripheral neuropathy.

Public Health Relevance

Our primary aim is to investigate the mechanism of cholinergic constraint that limits peripheral nerve growth, regeneration and plasticity in adults and to use this information to develop a novel therapeutic approach to reverse diabetic neuropathy. The goal is to promote rapid translation of our experimental findings to the treatment of patients with existing diabetic neuropathy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS081082-01A1
Application #
8577946
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Gwinn, Katrina
Project Start
2013-07-01
Project End
2018-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$328,138
Indirect Cost
$105,188
Name
University of California San Diego
Department
Pharmacology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093