Peripheral neuropathy is one of the major complications of diabetes. There is a compelling need to develop effective therapeutic approaches specifically designed to improve neurological function in the damaged peripheral nervous system after diabetes. Thymosin ?4 (T?4), a major intracellular G-actin- sequestering peptide, has multiple biological functions, including promotion of remodeling of injured and damaged tissues, and increasing angiogenesis after myocardial infarction. However, the role of T?4 in diabetic peripheral neuropathy has not been investigated. In a novel set of experiments, our data show that Tbeta4 remarkably improved sciatic nerve vascular function and peripheral nerve function in diabetic mice, indicating that T?4 may have a beneficial effect on the clinical treatment of diabetic peripheral neuropathy. In this application, we therefore seek to investigate the mechanisms underlying the therapeutic effects of T?4 on the treatment of diabetic peripheral neuropathy. We propose that T?4 by improving vascular function ameliorates diabetic peripheral neuropathy. Our hypotheses are: 1. Treatment with Tbeta4 improves neurological function of peripheral neuropathy in diabetic mice. 2. The Ang/Tie2 signaling pathway mediates the therapeutic effect of T?4 on neurovascular function in diabetic peripheral neuropathy. 3. The PI3K/Akt signaling pathway underlies the effect of Tbeta4 on Ang1/Ang2 expression. To investigate the effect of T?4 on neurological outcome, type II diabetic mice which develop severe peripheral neuropathy will be treated with T?4 at various time points after onset of diabetes. To investigate the molecular mechanisms that mediate Tbeta4-enhanced neurovascular function in diabetic mice, the effect of T?4 on expression of Ang/Tie2 and activation of PI3K/Akt signaling pathway will be examined. Using pharmacological inhibitors and siRNA gene knockdown techniques, we will investigate the cause-effect of the Ang/Tie2 and PI3K/Akt signaling pathways on regulating T?4-enhanced neurovascular function and axonal outgrowth. These studies are innovative and will provide new insight into mechanisms underlying the neurological dysfunction of diabetic peripheral neuropathy and lead to the development of a new treatment using T?4. Relevance Statement: Peripheral neuropathy often stemming from diabetes is a major disability affecting millions of Americans. In this proposal, employing preclinical studies in the diabetic animal, I seek to develop a novel treatment for peripheral neuropath using T?4. T?4 is currently in a phase II clinic trial for the treatment of patients with acute myocardial infarction. In this proposal, I also elucidate the molecular mechanism by which T?4 is therapeutically effective. This research will provide the essential pre-clinical data for translation to a phase 1 clinical trial.

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In this application, we propose to investigate whether thymosin ?4 (T?4)-ameliorated neurovascular dysfunction contribute to improvement of peripheral nerve recovery in experimental diabetic mice, which may provide a novel restorative therapy for diabetic peripheral neuropathy.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
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Jones, Teresa L Z
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Henry Ford Health System
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Jia, Longfei; Chopp, Michael; Wang, Lei et al. (2018) MiR-34a Regulates Axonal Growth of Dorsal Root Ganglia Neurons by Targeting FOXP2 and VAT1 in Postnatal and Adult Mouse. Mol Neurobiol 55:9089-9099
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Jia, Longfei; Wang, Lei; Chopp, Michael et al. (2018) MiR-29c/PRKCI Regulates Axonal Growth of Dorsal Root Ganglia Neurons Under Hyperglycemia. Mol Neurobiol 55:851-858
Wang, Lei; Chopp, Michael; Zhang, Zheng Gang (2017) PDE5 inhibitors promote recovery of peripheral neuropathy in diabetic mice. Neural Regen Res 12:218-219
Wang, Lei; Chopp, Michael; Szalad, Alexandra et al. (2016) Tadalafil Promotes the Recovery of Peripheral Neuropathy in Type II Diabetic Mice. PLoS One 11:e0159665
Jia, Longfei; Wang, Lei; Chopp, Michael et al. (2016) MicroRNA 146a locally mediates distal axonal growth of dorsal root ganglia neurons under high glucose and sildenafil conditions. Neuroscience 329:43-53
Wang, Lei; Chopp, Michael; Szalad, Alexandra et al. (2015) Sildenafil ameliorates long term peripheral neuropathy in type II diabetic mice. PLoS One 10:e0118134
Wang, Lei; Chopp, Michael; Jia, Longfei et al. (2015) Therapeutic Benefit of Extended Thymosin ?4 Treatment Is Independent of Blood Glucose Level in Mice with Diabetic Peripheral Neuropathy. J Diabetes Res 2015:173656

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