A translational approach for novel precision medicine models

About This Grant

PROJECT SUMMARY/ABSTRACT This collaborative proposal aims to identify novel molecular targets and mechanisms of treatment responses in AUD based on the evolving knowledge of a novel mitochondrial mechanism of epigenetic regulation and therapeutic target for AUD. Our cumulative findings and work from others showed: 1) Administration of LAC, a pivotal mitochondrial metabolite synthesized by the mitochondrial enzyme CrAT, ameliorates executive function, which is affected in AUD, and leads to the activation of specific HATs with the corresponding up-regulation of key genes (BDNF, mGlu2) in the hippocampus and ventral striatum, which are substrates implicated in AUD. 2) LAC also protects against AUD-related oxidative stress and neuroinflammation.3)In AUD patients, LAC reduces heavy drinking days and ameliorates cognitive function.Yet, the targets and mechanisms by which LAC-related mitochondrial metabolism contributes to the epigenetic regulation of treatment responses in AUD are unknown. Based on these compelling preclinical and clinical findings, we set out to test the central hypothesis that, by facilitating LAC-related activity of HATs, expression of CrAT in neuronal exosomes contribute to GEXR response in AUD. We have exciting preliminary data: i)Lowest CrAT expression in these specific exosomes, worst cognitive dysfunction;ii)Potential role of mitochondrial metabolism in HAT activity; iii)Specific baseline traits, including cognitive impulsivity, predict GEXR response; iv)Potential role of this novel signaling pathway in GEXR response. Aims:1)Determine the role of baseline and longitudinal changes in central mitochondrial metabolism of LAC for treatment response; 2) Determine the role of central mitochondrial metabolism of LAC in the epigenetic regulation of gene expression for treatment responses in AUD; we will further map topographical and cellular specificity of changes. In addition to the primary features of this mitochondrial signaling, we will assess a broader set of related mitochondrial, epigenetic and transcriptomic markers focusing on oxidative stress, glutamate, neurotrophic and inflammatory pathways in neuronal exosomes isolated from plasma of AUD subjects from the NIAAA-sponsored randomized controlled trial of Gabapentin enacarbil extended-release (GEXR, N=338). Utilizing mixed effect models, machine learning and clustering algorithms, we will model the separate and combined features of the primary and related pathways in predicting changes in heavy drinking days unadjusted for likelihood of responding to GEXR (primary analysis) and separately in causal inference models of likely responders. This study will also determine the relationship between central and peripheral molecular pathways of interest (peripheral RNAseq, samples and clinical characteristics are already available in our newest NIAAA-funded R01, PI Marmar), and how these pathways are modified by specific known AUD comorbidities. This contribution is significant as it will advance understanding of mechanisms and targets of AUD treatment and identify critical sex differences. Mechanistic insights into central and peripheral markers of GEXR response is impactful as they will aid to develop new treatment models targeted at endogenously adjusting mitochondrial metabolism to function within the epigenetic milieu for personalized AUD treatment. This proposal is also innovative as we use innovative approaches that we are using in other NIH-funded studies to link in vivo molecular targets and pathways to treatment responses over-time. We have a published track record in this area.