The etiology of diabetic peripheral neuropathy (DPN) involves an inter-related series of metabolic and vascular insults that ultimately contribute to sensory neuron degeneration. In the quest to pharmacologically manage DPN, small molecule inhibitors have targeted proteins and pathways regarded as """"""""diabetes specific"""""""" as well as others whose activity are altered in numerous disease states. These efforts have not yielded any significant therapies, due in part to the complicating issue that the biochemical contribution of these targets/pathways to the progression of DPN does not occur with temporal and/or biochemical uniformity between individuals. Thus, we have pursued the rational identification of a new molecular paradigm that offers a """"""""druggable"""""""" target and provides translational potential for effective medical management of DPN at various stages of disease progression. In complex, chronic neurodegenerative diseases such as Alzheimer's disease and DPN, it is increasingly appreciated that effective disease management may not necessarily require targeting a pathway or protein considered to contribute to disease progression. Alternatively, it may prove beneficial to pharmacologically enhance the activity of endogenous neuroprotective pathways to aid neuronal recovery and stress tolerance. To this end, we have synthesized a novel small molecule that activates an endogenous cytoprotective response by inhibiting the molecular chaperone, heat shock protein 90 (Hsp90). Hsp90 is the master regulator of the cytoprotective heat shock response, which upregulates expression of Hsp70 and antioxidant genes. Our lead compound is a non-toxic, bioavailable molecule called KU-32 and we provide evidence that it reverses multiple clinical indices of DPN, promotes the recovery and reinnervation of damaged sensory fibers into the epidermis, increases mitochondrial bioenergetics and decreases oxidative stress in models of Type 1 and Type 2 diabetes. Mechanistically, inhibiting Hsp90 with KU-32 induces other chaperones such as cytosolic Hsp70 and mitochondrial Hsp70 (mtHsp70) in diabetic dorsal root ganglia. Importantly, the efficacy of KU-32 requires Hsp70 since the drug is ineffective in reversing DPN in diabetic Hsp70 KO mice. In response to a comprehensive set of preliminary data gathered from animal and primary cell models, our broad hypothesis is that modulating Hsp70 and its paralogs can rescue sensory neurons from hyperglycemic stress by antagonizing aspects of glucose-induced mitochondrial dysfunction. To address this hypothesis, aim one will identify if reversing the clinical indices of DPN by KU-32 requires an Hsp70-dependent increase in mitochondrial bioenergetics of sensory neurons.
Aim 2 will determine if Hsp70 enhances mitochondrial bioenergetics by decreasing oxidative stress in adult sensory neurons.
Aim 3 will identify if Hsp70 and mtHsp70 augment mitochondrial function by increasing protein import in diabetic neurons. The outcomes of our work will provide fundamental molecular insight into how Hsp70 paralogs improve sensory neuron bio- energetics and validate that modulating molecular chaperones is a viable approach to medically manage DPN.
Approximately 24 million Americans are afflicted with diabetes and up to 60% of these patients may develop diabetic peripheral neuropathy. Although existing therapies can aid metabolic control of blood glucose levels, neuropathy may still develop. Therefore, additional therapies that decrease neuropathic symptoms and can complement agents that improve metabolic control are needed. This project focuses on investigating the translational potential and identifying the mechanism of action of a new class of small molecule therapeutics that we have developed and which reverse pre-existing symptoms of diabetic neuropathy.
|Zhang, Zheng; You, Zhenyuan; Dobrowsky, Rick T et al. (2018) Synthesis and evaluation of a ring-constrained Hsp90 C-terminal inhibitor that exhibits neuroprotective activity. Bioorg Med Chem Lett 28:2701-2704|
|Forsberg, Leah K; Anyika, Mercy; You, Zhenyuan et al. (2018) Development of noviomimetics that modulate molecular chaperones and manifest neuroprotective effects. Eur J Med Chem 143:1428-1435|
|Zhang, Xinyue; Li, Chengyuan; Fowler, Stephen C et al. (2018) Targeting Heat Shock Protein 70 to Ameliorate c-Jun Expression and Improve Demyelinating Neuropathy. ACS Chem Neurosci 9:381-390|
|Emery, S M; Dobrowsky, R T (2016) Promoting Neuronal Tolerance of Diabetic Stress: Modulating Molecular Chaperones. Int Rev Neurobiol 127:181-210|
|Ghosh, Suman; Liu, Yang; Garg, Gaurav et al. (2016) Diverging Novobiocin Anti-Cancer Activity from Neuroprotective Activity through Modification of the Amide Tail. ACS Med Chem Lett 7:813-8|
|Ghosh, Suman; Shinogle, Heather E; Galeva, Nadezhda A et al. (2016) Endoplasmic Reticulum-resident Heat Shock Protein 90 (HSP90) Isoform Glucose-regulated Protein 94 (GRP94) Regulates Cell Polarity and Cancer Cell Migration by Affecting Intracellular Transport. J Biol Chem 291:8309-23|
|Anyika, Mercy; McMullen, Mason; Forsberg, Leah K et al. (2016) Development of Noviomimetics as C-Terminal Hsp90 Inhibitors. ACS Med Chem Lett 7:67-71|
|Qian, Pengxu; He, Xi C; Paulson, Ariel et al. (2016) The Dlk1-Gtl2 Locus Preserves LT-HSC Function by Inhibiting the PI3K-mTOR Pathway to Restrict Mitochondrial Metabolism. Cell Stem Cell 18:214-28|
|Dobrowsky, Rick T (2016) Targeting the Diabetic Chaperome to Improve Peripheral Neuropathy. Curr Diab Rep 16:71|
|Ma, Jiacheng; Pan, Pan; Anyika, Mercy et al. (2015) Modulating Molecular Chaperones Improves Mitochondrial Bioenergetics and Decreases the Inflammatory Transcriptome in Diabetic Sensory Neurons. ACS Chem Neurosci 6:1637-48|
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