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Postdoctoral Fellow, University of Wisconsin-Madison

Employer
School of Pharmacy, University of Wisconsin-Madison
Location
Madison, Wisconsin
Salary
NIH NRSA Stipend Levels (0 years experience = $56,484)
Closing date
Jun 26, 2024

Postdoctoral Position in Neurodegeneration

Job Requirements:  A Ph.D. in neuroscience or related field.  Experience with transgenic animals and primary culture systems.  Good productivity during Ph.D. training.

Laboratory Research

Alzheimer’s Disease (AD) is the most common neurodegenerative disease, impacting roughly 6.7 million Americans currently and up to 13.8 million by 2060 without disease-modifying therapeutics. The greatest risk factor for developing AD is age.  AD and aging are associated with increased oxidative stress, mitochondrial dysfunction, inflammation, and protein aggregation, as well as impaired proteostasis. The laboratories overall work has focused on the Keap1 (Kelch-like ECH-associating protein 1)/Nrf2 (nuclear factor erythroid 2-related factor 2) pathway because activation of this pathway mitigates those AD associated mechanisms and thus poses an opportunity for novel therapeutic strategies. The protein-protein interaction (PPI) between Keap1 and Nrf2 sequesters Nrf2 in the cytoplasm. Disruption of this PPI allows for accumulation and nuclear translocation of Nrf2 where it binds to the antioxidant response element (ARE). Nrf2 binding to the ARE transcriptionally drives expression of several detoxifying and antioxidant genes.  This leads to increased resistance to mitochondrial dysfunction, oxidative stress, and inflammation. More recently, genes involved in maintaining and/or enhancing proteostasis through the UPS (ubiquitin proteasome system) and autophagy have been found to be Nrf2-dependent. Previous work in the laboratory found that Nrf2 activation/overexpression in astrocytes confers protection to neighboring neurons in vitro and in vivo. More recently, in collaboration with two other groups at the University of Edinburgh, we examined the impact of astrocytic Nrf2 activation in two mouse models of AD (APP/PS1 and MAPTP301S). Transgenic mice using the glial fibrillary acidic protein (GFAP) to drive Nrf2 expression in astrocytes (GFAP-Nrf2 mice) were crossed with the two AD models1. In both cases, there was a significant attenuation of pathology with reduced tau phosphorylation and neuronal loss in MAPTP301S mice and a 70-80% reduction in amyloid-beta (Aβ) and plaque load in APP/PS1 mice.  These data clearly demonstrate the high therapeutic potential for Nrf2-activating compounds/biologics in AD. Current projects include: 1) determining the neuroprotective mechanisms mediated by astrocytic Nrf2 activation; 2) the role of Nrf2 in microglial activation; 3) viral-mediated delivery of Nrf2 to neurons and astrocytes; and 4) based on a recent publication2, the development of Keap1/Nrf2 PPI disruptors for activation of the Nrf2 pathway.

  1. Jiwaji Z*, Tiwari SS*, Avilés-Reyes RX*, Hooley M*, Hampton D, Torvell M, Johnson DA, McQueen J, Baxter P, Sabari-Sankar K, Qiu J, He X, Fowler J, Febery J, Gregory J, Rose J, Tulloch J, Loan J, Story D, McDade K, Smith AM, Greer P, Ball M, Kind PC, Matthews PM, Smith C, Dando O, Spires-Jones TL, Johnson JA#, Chandran S#, Hardingham GE#. (2022). Reactive astrocytes acquire neuroprotective as well as deleterious signatures in response to Tau and Aß pathology. Nat Commun. 2022 Jan 10;13(1):135.*Equal contribution and #Corresponding authors.
  2. Carrow, KP, Hamilton, HL, Hopps, MP, Li, Y, Qiao, B, Payne, NC, Thompson, MP, Zhang, X, Magassa, A, Fattah, M, Agarwal, S, Vincent, MP, Buyanova, M, Bertin, PA, Mazitschek, R, Olvera de la Cruz, M, Johnson, DA#, Johnson, JA#, Gianneschi, NC#. (2024) Inhibiting the Keap1/Nrf2 Protein-Protein Interaction with Protein-Like Polymers. Adv Mater. 2024 Jan 19; e2311467. #Corresponding authors.

Publications: https://scholar.google.com/citations?user=n76H-P0AAAAJ hl=en

Please contact: Jeffrey A. Johnson, Ph.D., University of Wisconsin, Phone: (608) 262-2893; e-mail: jeffrey.johnson@wisc.edu

Website: https://apps.pharmacy.wisc.edu/sopdir/jeffrey_johnson/index.php

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