BLR&D Research Career Scientist Award Application

摘要 帕西内蒂博士的研究目标是研究在衰老过程中发生的生物过程 认知功能正常的受试者会转化为阿尔茨海默病(AD)的最早期阶段和 然后是弗兰克痴呆症。帕西内蒂博士在包括以下期刊的356篇手稿中发表了他的关键工作 《生物化学、自然、神经元和细胞》杂志。帕西内蒂博士的出版物具有的H影响因子 根据谷歌学者的数据，这两个词被引用了12000次。以下是他的研究的简要概述： 阿尔茨海默病(AD)和2型糖尿病(T2D)帕西内蒂博士认为T2D是主要风险之一 可能部分通过表观遗传机制影响AD神经病理和突触可塑性的因素。在一个 最近的全基因组关联研究发现，T2D患者的一个亚群有一种遗传 基于共同T2D/AD单核苷酸多态性证据的AD易感性 基因途径涉及染色质修饰酶等。这些研究将提供 保护部分T2D受试者认知健康的新治疗目标的基础，请访问 开发AD的风险。 2)药物的发现和再利用。神经毒性寡聚体β-淀粉样蛋白(Aβ)多肽和错误折叠的tau 与突触可塑性的破坏有关，部分参与了发病和死亡的机制 认知恶化的进展，最终导致阿尔茨海默病。使用结构-活性关系(SAR) 帕西内蒂博士的实验室正在“重建”缺乏心血管副作用的新型抗高血压药物 但具有增强抗Aβ寡聚活性的作用。改变药物用途有几个优点 新型药物，因为它们在耐受性和安全性方面已经有了很好的特点。 3)轻度颅脑损伤(MTBI)和创伤后应激障碍(PTSD)的生物标志物。Dr。 帕西内蒂确定了生物标志物，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和创伤后应激障碍。帕西内蒂博士的实验室报告了四个非编码微粒子的差异表达 退伍军人中的RNA能够区分患有创伤后应激障碍的受试者，但不能区分创伤性脑损伤。这样的生物标记物可能会提供新的 选择患有合并创伤性脑损伤/创伤后应激障碍的患者的基准，这些患者也是AD的高危人群。 4)分子整合神经弹性。帕西内蒂博士被授予P50研究中心赠款 “分子整合神经复原力”，其主要目标是了解 新近发现的多酚类化合物可以提高对压力诱导的心理和心理反应的韧性 认知障碍。最重要的是，该实验室目前正在利用研究中心在 与旨在预防和治疗的安全性和有效性研究有关的机械性调查 提高海湾战争多酚退伍军人认知和心理弹性的方法 “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)照顾者健康计划。帕西内蒂博士的实验室调查了基于正念的压力减轻 照顾者(MBSR)培训课程可能会提高非专业照顾者的心理韧性 阿尔茨海默病患者。在转录学研究中，我们发现了一组91个生物标志物基因 其在基于正念的压力减轻(MBSR)前外周血单核细胞中的含量预测了 护理对象从干预中受益的准确率为94.7%。这些研究提供了对 MBSR的健康益处机制和开发个性化药物治疗方法的基础 应用MBSR促进痴呆患者照顾者的心理和认知弹性， 特别是退伍军人照顾者，他们有很高的压力导致的心理和认知损伤的风险。 综上所述，帕西内蒂博士的研究重点是确定神经退行性变的分子基础 疾病和新疗法的靶点与退伍军人管理局的使命高度相关，最终目标是 确定可转化为改善退伍军人护理的新治疗策略。

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.