Blair Lab

Running, talking, breathing, remembering…

These things are coordinated by thousands of different proteins at work in our cells. Among them is a group of sentinels called chaperones that ensure the propriety of the majority of cellular proteins and resultant cellular functions. Our lab is focused on the role of chaperones in a group of more than 15 neurological degenerative diseases collectively termed “tauopathies”, the most common being Alzheimer’s disease. We hope that an understanding of chaperone function will enable therapeutic strategies that increase quality of life, halt disease progression and ultimately cure neurodegenerative diseases. 

Research Overview

Our lab is focused on preserving brain health through the regulation of the cell’s natural defense system, the molecular chaperone network. This network gets out of balance through aging and disease, which contribute to neuropsychiatric disorders like post-traumatic stress disorder (PTSD) and Alzheimer’s disease. Our group is systematically interrogating how specific chaperones preserve or destroy protein aggregates in Alzheimer’s disease and how the balance of one particular chaperone, FKBP51, impacts stress response for stress-related mental health disorders. In addition to expanding our knowledge about the biology and identifying targets, we are working to develop therapeutics to restore the balance through the regulation of molecular chaperones and therefore preserve brain health at the same time. We are confident that this strategy will yield tractable therapies to halt or possibly reverse Alzheimer’s disease progression as well as help reduce symptoms associated with PTSD and depression.

Learn more about our research

Laura Blair

PhD

Principal Investigator and Associate Professor

Meet the Team

Latest News

Featured Publications

  • Gebru, Niat T, Jennifer Guergues, Laura A Verdina, Jessica Wohlfahrt, Shuai Wang, Debra S Armendariz, Marsilla Gray, et al. (2024) 2024. “Fkbp5 Gene Deletion: Circadian Rhythm Profile and Brain Proteomics in Aged Mice.”. Aging Cell 23 (12): e14314. https://doi.org/10.1111/acel.14314.
    Publisher's Version

    FKBP51, also known as FK506-binding protein 51, is a molecular chaperone and scaffolding protein with significant roles in regulating hormone signaling and responding to stress. Genetic variants in FKBP5, which encodes FKBP51, have been implicated in a growing number of neuropsychiatric disorders, which has spurred efforts to target FKBP51 therapeutically. However, the molecular mechanisms and sub-anatomical regions influenced by FKBP51 in these disorders are not fully understood. In this study, we aimed to examine the impact of Fkbp5 ablation using circadian phenotyping and molecular analyses. Our findings revealed that the lack of FKBP51 did not significantly alter circadian rhythms, as detected by wheel-running activity, but did offer protection against stress-mediated disruptions in rhythmicity in a sex-dependent manner. Protein changes in Fkbp5 KO mice, as measured by histology and proteomics, revealed alterations in a brain region- and sex-dependent manner. Notably, regardless of sex, aged Fkbp5 KOs showed elevated MYCBP2, FBXO45, and SPRYD3 levels, which are associated with neuronal-cell adhesion and synaptic integrity. Additionally, pathways such as serotonin receptor signaling and S100 family signaling were differentially regulated in Fkbp5 KO mice. Weighted protein correlation network analysis identified protein networks linked with synaptic transmission and neuroinflammation. The information generated by this work can be used to better understand the molecular changes in the brain during aging and in the absence of Fkbp5, which has implications for the continued development of FKBP51-focused therapeutics for stress-related disorders.

  • Gebru, Niat T, David Beaulieu-Abdelahad, Danielle Gulick, and Laura J Blair. (2024) 2024. “FKBP51 Overexpression in the Corticolimbic System Stabilizes Circadian Rhythms.”. Cell Stress & Chaperones 30 (1): 22-32. https://doi.org/10.1016/j.cstres.2024.12.003.
    Publisher's Version

    Circadian rhythm disruptions have been associated with a wide range of health issues and complications, including an increased risk of circadian rhythm sleep disorders (CRSDs). CRSDs are common among individuals who have been through a traumatic event, particularly in those who have post-traumatic stress disorder (PTSD). Allelic variations in the gene encoding for FK506-binding protein 51 (FKBP51) can increase the susceptibility for PTSD and other stress-related disorders following trauma. At least one of these variants increases the levels of FKBP51 following stress through a glucocorticoid receptor-mediated process. Here, we used a mouse model that overexpresses human FKBP51 throughout the forebrain, rTgFKBP5, to investigate if elevated FKBP51 contributes to circadian rhythm disruption. Surprisingly, our findings indicate a greater rhythm amplitude and decreased rhythm fragmentation in rTgFKBP5 mice, particularly females, compared to controls. Female rTgFKBP5 mice also showed higher corticosterone levels basally and following stress exposure. Overall, this study associates FKBP51 overexpression with beneficial circadian rhythm outcomes.

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