PTEN knockdown: a novel strategy to reverse diabetic neuropathy
This proposal is aimed at a novel regenerative approach toward diabetic peripheral neuropathy using PTEN inhibition or knockdown. Currently there is no therapy available to reverse neuropathic damage (loss of sensation, neuropathic pain, risk of lower limb ulceration) in diabetic subjects. The Zochodne laboratory has discovered a novel and robust approach toward accelerating the growth of adult peripheral sensory neurons by blocking a regeneration roadblock, PTEN. PTEN (phosphatase and tensin homolog deleted on chromosome ten) is a tumour suppressor molecule that blocks activation of growth programs in cells. It is widely expressed in adult sensory neurons and appears to be upregulated in diabetes. Our laboratory has shown that localized and temporary PTEN inhibition pharmacologically or using nonviral siRNA transfection dramatically increases the growth of adult sensory neurons in vivo and in vitro. Our overall hypothesis is that inhibition or knockdown of PTEN may be associated with reversal of diabetic neuropathy. Our aims in this pilot and feasibility proposal are: 1. To evaluate expression of PTEN and downstream molecules in type 1 and 2 experimental diabetic neuropathy models in mice; 2: To evaluate the impact of PTEN pharmacological or siRNA knockdown on experimental type 1 and 2 diabetic neuropathy in mice. In our laboratory we evaluate experimental neuropathy using electrophysiological, behavioural and morphometric endpoints including epidermal axon density. We propose a rigorous reversal interventional protocol. Temporary and localized PTEN inhibition [nb/only systemic or permanent knockdown theoretically impacts tumorogenesis] is carried out using a pharmacological inhibitor and we have pioneered an exciting nonviral (potentially translatable to humans) siRNA knockdown paradigm.

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