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Alexander (Alex) Glebov-McCloud

Address: 2-400 BSBAlexander Glebov-McCloud photo
Phone: (319) 384-4447
Email: alexander-glebov-mccloud@uiowa.edu

Mentor: Stefan Strack, PhD

Undergraduate Institution: Grinnell College

Graduate Program: Molecular Medicine

Year Entered Into Program: 2019

Research Description

The Role of Drp1-Dependent Mitochondrial Fission in Peripheral Diabetic Neuropathy (PDN)

Peripheral diabetic neuropathy (PDN) is a frequent complication of diabetes that affects over half of diabetes patients in North America. Patients with PDN frequently experience deterioration of distal sensory axons, which manifests as symptoms such as loss of sensation in the low extremities. This loss of sensation hinders patients’ abilities to detect injury to their low extremities, ultimately increasing the risk of severe infections and gangrene. While its symptoms are severe, there are few, if any, disease-modifying approaches to treat peripheral diabetic neuropathies. 

One crucial factor that causes sensory axon deterioration in PDN is excess production of reactive oxygen species (ROS). Another factor that contributes to PDN is mitochondrial malfunction in sensory axons. More specifically, mitochondrial malfunction in diabetes is characterized by disruption of the mitochondrial fission and fusion equilibrium, which can result in neuronal death. The GTPase Drp1 regulates mitochondrial fission, and Drp1 itself is regulated by protein kinase A (PKA) and protein phosphatase 2A (PP2A) via reversible phosphorylation. PKA inhibits Drp1 via phosphorylation, which promotes mitochondrial elongation and ultimately neuronal survival. On the other hand, PP2A activates Drp1 via dephosphorylation, thereby promoting mitochondrial depolarization and neurotoxicity. PP2A is recruited to the outer mitochondrial membrane by its regulatory Bβ2 subunit.

Preliminary data from our lab shows that both type 1 and type 2 diabetes models of Bβ2 knockout (Bβ2 KO) mice are resistant to PDN, indicating that the development of PDN is influenced by abnormal regulation of Drp1. We hypothesize that dysregulation of the mitochondrial fission/fusion equilibrium contributes to the pathogenesis of PDN, and that inhibition of Drp1-dependent mitochondrial fission by Bβ2 KO provides neuroprotection via improvement of mitochondrial metabolism, reduction of ROS, modulation of mitochondrial Ca2+ transport, and enhanced regeneration of sensory axons.

Awards

  • Fellowship appointment on the Pharmacological Sciences Training Program (NIH T32 GM067795), University of Iowa, 2020-present