BLR&D Research Career Scientist Award Application

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SUMMARY The goals of Dr. Pasinetti’s research is to investigate the biological processes that occur during aging when subjects with normal cognitive function convert into the very earliest stages of Alzheimer’s disease (AD) and then to frank dementia. Dr. Pasinetti has published his pivotal work in 356 manuscripts in journals including Journal of Biochemistry, Nature, Neuron, and Cell. Dr. Pasinetti’s publications have an H impact factor of 64 and are cited 12,000 times according to Google Scholar. A brief synopsis of his research is provided below: 1) Alzheimer’s disease (AD) and type 2 diabetes (T2D) Dr. Pasinetti identified T2D as one of the major risk factors that might affect AD neuropathology and synaptic plasticity in part through epigenetic mechanisms. In a recent genome wide association study, we found a subpopulation of individuals with T2D have a genetic predisposition to AD based on the evidence of shared common T2D/AD single nucleotide polymorphisms in gene pathways involved in chromatin modification enzymes, among others. These studies will provide the basis for novel therapeutic targets towards the preservation of cognitive health in a subset of T2D subjects at risk for developing AD. 2) Drug discover and repurposing. Neurotoxic oligomeric β-amyloid (Aβ) peptides and misfolded tau have been implicated in disruption of synaptic plasticity, contributing in part to mechanisms underlying onset and progression of cognitive deterioration and eventually AD dementia. Using a structure-activity relationship (SAR) approach, Dr. Pasinetti’s laboratory is “reconstructing” novel antihypertensive drugs lacking cardiovascular side effects but with enhanced anti-Aβ oligomerization activity. Repurposing drugs has several advantages over novel drugs since they are already well-characterized in respect to tolerability and safety profile. 3) Biomarkers of mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD). Dr. Pasinetti identified biomarkers to help diagnose two of the major “signature injuries” of the recent wars in Iraq and Afghanistan: mTBI and PTSD. Dr. Pasinetti’s lab reported differential expression of four non-coding micro RNAs in Veterans able to distinguish subjects with PTSD but not TBI. Such biomarkers could provide novel benchmarks in patient selection with comorbid TBI/PTSD who are also at high risk for AD. 4) Molecular Integrative Neuroresilience. Dr. Pasinetti was awarded a P50 Research Center Grant on “Molecular Integrative Neuroresilience” with the primary goal of understanding the mechanisms through which recently identified polyphenolic compounds may promote resilience against stress-induced psychological and cognitive impairment. Most importantly, the lab is currently leveraging the Research Center Activities in mechanistic investigations related to safety and efficacy studies aimed at preventative and therapeutic approaches to promote cognitive and psychological resilience in Gulf War Illness Veterans with polyphenolic “natural drugs” compounds in collaboration with the VA War Related Illness and Injury Study Center (WRIISC). 5) Caregivers Health Program. Dr. Pasinetti’s lab investigated whether a mindfulness-based stress reduction (MBSR) training course for caregivers may improve the psychological resilience of non-professional caregivers of Alzheimer's disease patients. In transcriptomic studies we found a panel of 91 ‘‘predictor’’ biomarker genes whose contents in PBMCs prior to mindfulness-based stress reduction (MBSR) predicted the likelihood of caregiver subjects to benefit from the intervention with 94.7% accuracy. These studies provide insight into the mechanisms of health benefits of MBSR and a basis for developing a personalized medicine approach for applying MBSR for promoting psychological and cognitive resilience in caregivers of dementia patients, especially VA caregivers, who are at high risk for stress-induced psychological and cognitive impairment. Taken together, the focus of Dr. Pasinetti’s research determining the molecular basis of neurodegenerative disorders and targets for novel therapies is highly relevant to the mission of the VA with the ultimate goal of identifying novel treatment strategies that can be translated to improve the care of Veterans.