College of Medicine
184 Rightmire Hall
1060 Carmack Road
Columbus, OH 43210
Postdoc positions are available
Education and Training
PhD: Tufts University Medical School
Postdoctoral Training: Cornell Medical College
- School of Biomedical Science Excellence in Research and Teaching, Ohio State University (2008)
- Whitehall Foundation Research Award (1999-2002)
- Career Development Award from American Cancer Society (2000-2003)
- Young Investigator Award from the National Alliance for Research on Schizophrenia and Depression (1999-2000)
- Postdoctoral Fellowship, the National Multiple Sclerosis Society (1994-1997)
- First Prize, Charlton Fund Student Research Scientist Poster Competition, Tufts Univ. School of Medicine
- Committee on Grants-in-Aid of Research, Sigma Xi
Drug discovery for Alzheimer’s disease with JNK3-selective, brain penetrating small molecule(s) that are orally bioavailable: Our data suggest a model wherein JNK3 is cyclically activated as the primary summing node of multiple positive feedback paths in Aβ peptide signaling. Initially, JNK3 phosphorylates APP to induce rapid endocytosis and processing to produce pathological Aβ42. Aβ42 then induces translational block by activating AMP-activated protein kinase (AMPK), which leads to ER stress, which further activates JNK3, thereby establishing a positive feedback loop. These data suggest that blocking JNK3 activation at any point can potentially halt or slow the subsequent progression of the disease. We have developed several orally bioavailable JNK3-selective small molecule inhibitors that cross the blood brain barrier efficiently, and some of them are being tested in ad models. This project is currently funded by RO1AG055059 until 2022.
Understanding the role of metabolic stress in microglial function in AD: Being a universal sensor of metabolic homeostasis, AMPK activation by Aβ42 suggests that Aβ42 can disrupt normal glucose homeostasis even when neurons are in glucose/nutrient-rich medium. This is in line with human data, which illustrate that glucose hypometabolism in the brain is a phenomenon observed decades before AD symptoms appear. In an effort to characterize metabolic changes in AD mice, we have conducted longitudinal metabolomics study using serum, urine, and brain samples from 5XFAD mice. Our preliminary data suggest that there might be a dysfunction in the glycolytic pathway as the AD pathology becomes more pronounced with age. In support, we found aberrant activation of pyruvate kinase M2 (PKM2) in human cortical samples from AD. PKM2 is expressed exclusively among microglia in AD mice, and its expression levels increase with the progression of the AD pathology in mice. Pharmacological activation of PKM2 in primary microglia enhances Aβ42 uptake, which correlated with enhanced glycolysis and inhibition of oxidative phosphorylation. These results suggest modulating microglial energetics can influence AD pathology. We are examining the role of PKM2 activation in microglia in AD mice using conditional knockout strategies.
Understanding the mechanism by which Aβ42 activates AMPK: Our preliminary data illustrate that the kinetics of AMPK activation by Aβ42 is identical to that by 2-deoxy glucose in mature neuronal cultures. In support, AMPK activation is increased in AD mice. With hypothesis that Aβ42 inhibits normal glucose homeostasis by activating AMPK, we sought to decipher the underlying mechanism. We found that JNK3 that is activated by Aβ42 directly phosphorylates AMPKα subunits at S356 in α1 and S345 in α2. We have generated knock-in mutant mice in AMPK α1 and α2 subunits and are in the process of analyzing its phenotype in central and peripheral metabolism in AD background.
Role of proNGF and p75 signaling in loss of bladder control after spinal cord injury: Loss of bladder control is a challenging outcome facing spinal cord injured patients. Our data illustrate that systemic blocking of proNGF signaling through p75 with a CNS-penetrating small molecule p75 inhibitor resulted in significant improvement in bladder function after spinal cord injury (SCI) in mice. The usual hyperreflexia was attenuated with normal bladder pressure, and automatic micturition was acquired weeks earlier than in the controls. The improvement was associated with increased excitatory input to the spinal cord, in particular onto the tyrosine hydroxylase+ fibers in the dorsal commissure. The drug also had an effect on the bladder itself, as the urothelial hyperplasia and detrusor hypertrophy that accompanies SCI was largely Comment [ss5]: Delete and replace with what I entered prevented. Urothelial cell loss that precedes hyperplasia was solely dependent on p75 in response to urinary proNGF that is detected after SCI in rodents and humans. Surprisingly, death of urothelial cells and ensuing hyperplasic response was beneficial to functional recovery. Deleting p75 from the urothelium prevented urotheial death, but resulted in worsening of bladder function after SCI. These results unveil a dual role of proNGF-p75 signaling in the bladder function under pathological conditions with a CNS effect overriding the peripheral one. This project is currently funded by RO1DK117231 until 2023.
Novel role of p75 in Schwann cell metabolism: Loss of p75 neurotrophin receptor in global knockout mice (p75KO) results in reduced heat sensitivity. This phenotype has been mainly attributed to a ~30% loss of sensory neurons from the dorsal root ganglia (DRG) during development, which was supported by a 2-3 fold decrease in NGF sensitivity of p75KO sensory neurons, when they are cultured in isolation without Schwann cells. P75 is, however, expressed by both sensory neurons and Schwann cells; to better understand the role of p75 in these two cell types, we generated conditional knockout mice lacking p75 in Schwann cells or in neurons.
Upon deleting p75 selectively in sensory neurons (Thy1-cre:p75fl/fl) or Schwann cells (Dhh-cre: p75fl/fl), we found that p75 in Schwann cells contributes to nociceptive behavior: Dhh- cre: p75fl/fl mice exhibited decreased heat sensitivity. This phenotype was supported by a surprising 30% loss of sensory neurons irrespective of their subtype specificity in adult Dhh-cre: p75fl/fl mice but not in Thy1-cre:p75fl/fl mice. There was no effect on Schwann cell survival and myelination. Our data suggest that the loss of sensory neurons is in part due to an increased production of reactive cholesterol precursors in Schwann cells as a result of disruption in cholesterol metabolism that normally relies on a novel interaction between p75 and ErbB2.
This project is funded by RO1DK120108 until 2023, and a manuscript on the project is currently under review.