Grant: Operating Grant

Background. Diabetic neuropathy is a major complication of diabetes with no effective therapy. The incidence of peripheral nerve damage in diabetic patients can be 50% or higher and leads to incapacitating pain, sensory loss, foot ulceration (up to 2 million North Americans have this complaint) and lower extremity amputation often follows (accounts for 90,000 cases each year in North America). A primary feature of the disease is loss of nerve endings leading to denervation of the skin and subsequent sensory loss. Our recent work shows that mitochondria, the ells energy generator, are abnormal in sensory neurons, the cells that innervate the peripheral tissues, in diabetic rodents. Preliminary work. We show for the first time that an intracellular signaling pathway comprising AMP-activated protein kinase (AMPK), that senses the energy demands of cells and regulates mitochondrial function accordingly, is dysfunctional in animals models of type 1 and 2 diabetes. Hypothesis. We propose that in neurons under diabetic conditions the excess glucose causes AMPK to be deactivated and results in diminishment of mitochondrial activity. An innovative translational component of our work is the identification of cytokine treatment or blockade of the muscarinic acetylcholine type 1 receptor (M1R) as novel mechanisms to activate the AMPK pathway and mitochondrial function in neurons. Objectives. This proposal will determine if the AMPK signaling pathway is indeed a central regulator of mitochondrial function in neurons in diabetes. We wish to: (i)characterize the regulatory pathways that control this critical signaling axis, (ii)investigate global changes in gene expression, (iii)identify novel means of modulating pathway activity, for example using antimuscarinic drugs, in order to initiate new therapeutic opportunities for diabetic sensory neuropathy.