Dr. J. Josh Lawrence - Faculty Page

Research Interests:

Nutrigenomics, cellular and synaptic physiology of Alzheimer’s disease, role of excitation/inhibition balance in disease states, hippocampal learning and memory circuitry, GABAergic inhibition, cell type specificity of neuromodulation, antioxidant depletion over lifespan, neuroinflammation, effects of diet on healthy aging, computational neuroscience, bioinformatics

Current Projects

Collapse of Vitamin A homeostasis in Alzheimer’s Disease pathogenesis and progression.
In this project, we are determining how disruption of Vitamin A homeostasis occurs in Alzheimer’s disease (AD). Early stages of AD (mild cognitive impairment) show elevated activity and hyperexcitability of the dentate gyrus of the hippocampus are accompanied by a failure to detect novelty. However, causal upstream signaling mechanisms occurring in DG circuits during AD pathogenesis remain poorly understood. Mitochondria produce excess reactive oxygen species (ROS), which damages proteins, lipids, and DNA ¾ a process termed oxidative stress. Dietary antioxidants (AOs) normally scavenge excess ROS, preventing oxidative stress.  However, in disease states, we hypothesize that the homeostatic balance between antioxidants and oxidative stress is disrupted due to antioxidant depletion. The antioxidant all-trans retinoic acid (ATRA), the active form of dietary retinol, plays a dual role not only as a ROS scavenger but also as a hormone-like nuclear receptor ligand, binding as an agonist to the retinoic acid receptor (RAR). We propose that ATRA depletion in memory circuits is an early event in AD pathogenesis, leading to reduced occupancy of RARs, excess ROS, and mitochondrial dysfunction across hippocampal cell types, accelerating amyloidosis, network hyperexcitability, and cognitive impairment. We use an innovative multidisciplinary approach that uniquely combines DG-dependent learning, single cell transcriptomics, measures of OS and mitochondrial dysfunction, and functional circuit analysis in two AD mouse models. The project is currently funded by an NIH R01 grant.

“Reverse aging” the genome to prevent Alzheimer’s Disease-related learning deficits.
Prominent roles of oxidative stress in Alzheimer’s disease (AD) imply that antioxidant depletion is a critical mechanism occurring at prodromal stages. Yet, to date, clinical trials involving antioxidant supplementation have paradoxically failed. Several histone deacetylases (HDACs) have been shown to be upregulated, providing evidence that deacetylation is a molecular mechanism that leads to transcriptional repression in AD. We hypothesize that HDAC inhibition is required to restore function of key transcription factors that support hippocampal-dependent learning. This project tests the idea that vitamin A supplementation and HDAC inhibition act synergistically to restore transcription of vitamin A-sensitive genes for hippocampal learning and memory operations. We use an innovative multidisciplinary approach that uniquely combines hippocampal-dependent learning, transcriptomic/metabolomic/lipidomic profiling, and multi-omic integration in two AD mouse models.  The project is currently funded by an NIH R01 grant.

Vitamin D deficiency in health disparities, co-morbidities, and cognitive decline.
Vitamin D (VD) deficiency is associated with age, health disparities, and related co-morbidities that increase the risk of Alzheimer’s disease (AD). Age and skin pigmentation interferes with VD synthesis. Therefore, aging dark-skinned individuals (African Americans and Hispanics) are particularly at risk for VD deficiency. Moreover, VD is a lipid soluble vitamin; therefore, overweight/obesity further increases the risk of VD deficiency.  Our current projects examine relationships between VD deficiency and co-morbidities among Hispanics using the Garrison Institute on Aging’s Project FRONTIER database. The knowledge obtained will, through future clinical trials and community-based interventions, increase visibility of readily available VD supplements for therapeutic interventions, prevention, and/or mitigation of VD-related cognitive and co-morbidities, thereby reducing AD risk.

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