BLR&D Research Career Scientist Award Application

总结 Pasinetti博士的研究目标是调查衰老过程中发生的生物学过程， 具有正常认知功能的受试者转变为阿尔茨海默病（AD）的最早期， 然后是弗兰克痴呆Pasinetti博士在356份手稿中发表了他的关键工作，包括 生物化学杂志，自然，神经元和细胞。Pasinetti博士的出版物的H影响因子为64 根据Google Scholar的数据，被引用了12,000次。他的研究简要概述如下： 1)阿尔茨海默病（AD）和2型糖尿病（T2 D）Pasinetti博士将T2 D确定为主要风险之一， 可能通过表观遗传机制部分影响AD神经病理学和突触可塑性的因素。中 最近的全基因组关联研究，我们发现T2 D患者的一个亚群具有遗传 AD易感性的基础上共享共同的T2 D/AD单核苷酸多态性的证据， 染色质修饰酶的基因途径等。这些研究将提供 在T2 D受试者亚组中保护认知健康的新型治疗靶点的基础 发展AD的风险。 2)药物发现和再利用。神经毒性寡聚β-淀粉样蛋白（Aβ）肽和错误折叠的tau蛋白具有神经毒性， 与突触可塑性的破坏有关，部分导致发病机制， 认知功能恶化，最终导致AD痴呆。构效关系（SAR） Pasinetti博士的实验室正在“重建”缺乏心血管副作用的新型降压药 作用，但具有增强的抗A β寡聚化活性。重新使用药物有几个优点， 新药，因为它们在耐受性和安全性方面已经得到了很好的表征。 3)轻度创伤性脑损伤（mTBI）和创伤后应激障碍（PTSD）的生物标志物。博士 Pasinetti确定了生物标志物，以帮助诊断最近伊拉克战争中的两个主要“标志性损伤” 和阿富汗：mTBI和PTSD。Pasinetti博士的实验室报告了四种非编码微 退伍军人中的RNA能够区分PTSD受试者，但不能区分TBI。这些生物标志物可以提供新的 在患有TBI/PTSD共病的患者选择中，这些患者也处于AD的高风险中。 4)分子整合神经复原力。Pasinetti博士被授予P50研究中心补助金， “分子综合神经弹性”的主要目标是了解通过它的机制， 最近发现的多酚化合物可能会促进对压力引起的心理和心理恢复力， 认知障碍最重要的是，该实验室目前正在利用研究中心的活动， 与安全性和有效性研究相关的机制研究，旨在预防和治疗 用多酚类物质促进海湾战争疾病退伍军人认知和心理复原力的方法 “天然药物”化合物与退伍军人事务部战争相关疾病和伤害研究中心（WRIISC）合作。 5)护理人员健康计划。Pasinetti博士的实验室调查了基于正念的减压方法 （MBSR）培训课程的照顾者可能会提高非专业照顾者的心理弹性 老年痴呆症患者。在转录组学研究中，我们发现了一组91个“预测”生物标志物基因， 在正念减压（MBSR）之前，其在PBMC中的含量预测了 护理人员受试者从干预中受益，准确率为94.7%。这些研究提供了深入了解 正念减压疗法的健康益处的机制和开发个性化医疗方法的基础， 应用正念减压疗法促进痴呆患者照顾者的心理和认知复原力， 特别是VA照顾者，他们处于压力引起的心理和认知障碍的高风险中。 综上所述，Pasinetti博士的研究重点是确定神经退行性疾病的分子基础， 疾病和新疗法的目标与VA的使命高度相关，其最终目标是 确定新的治疗策略，可以转化为改善退伍军人的护理。

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.