Epigenetic Mechanisms in human memory quantified by non-invasive PET imaging

通过非侵入性 PET 成像量化人类记忆中的表观遗传机制

• 批准号: 9262133
• 负责人: Jacob M. Hooker
• 金额: $ 25.65万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-15 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9262133
• 关键词: Affect; Age; Age-associated memory impairment; Aging; Aging-Related Process; Alzheimer' s Disease; Animal Model; Animals; Applications Grants; Autopsy; Basic Science; Behavior; Binding; Biochemistry; Brain; Brain Diseases; Central Nervous System Diseases; Cerebellum; Chemicals; Chromatin; Chromosome Structures; Cognition; Cognitive; Collaborations; Control Animal; DNA; Data; Data Set; Development; Diagnostic; Discipline; Disease; Drug Targeting; Elements; Environment; Enzymes; Epigenetic Process; Exploratory/Developmental Grant; FDA approved; Family; Frontotemporal Dementia; Functional disorder; Gene Expression; Goals; HDAC4 gene; Hippocampus (Brain); Histone Deacetylase; Histone Deacetylase Inhibitor; Human; Human Volunteers; Image; Impaired cognition; Individual; Intervention; Knowledge; Lead; Learning; Life; Life Experience; Link; Location; Magnetic Resonance; Magnetic Resonance Imaging; Maps; Measurement; Measures; Mediator of activation protein; Memory; Memory impairment; Mental Depression; Mental disorders; Motivation; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Plasticity; Neurons; Neurosciences; Pathogenesis; Patient Selection; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Play; Positron-Emission Tomography; Proteins; Reporting; Research; Rest; Rewards; Role; Scanning; Schizophrenia; Short-Term Memory; Structure; System; Technology; Testing; Therapeutic; Therapeutic Trials; Time; Tissue Sample; Tissues; Tracer; Translating; Validation; Variant; Work; Zinc; aged; aging brain; base; brain dysfunction; brain tissue; clinical imaging; cognitive function; cohort; density; drug discovery; epigenetic drug; high reward; high risk; imaging agent; imaging probe; imaging study; improved; in vivo; insight; man; mouse model; multidisciplinary; neural circuit; neurodevelopment; neuropathology; neuropsychiatric disorder; neurotransmission; non-invasive imaging; normal aging; novel therapeutics; pathological aging; pre-clinical; public health relevance; radiotracer; relating to nervous system; response; small molecule; success; uptake; young adult

 DESCRIPTION (provided by applicant): Histone deacetylase (HDAC) enzymes are zinc-dependent chromatin modifying proteins that have emerged as an important lead in understanding CNS dysfunction. To date, HDAC expression has been measured in a small number of postmortem brain tissue samples from healthy and diseased patients affected by brain disorders including schizophrenia, depression and Alzheimer's Disease (AD) and provides evidence that altered expression of HDACs in at least cortex, hippocampus and cerebellum, may play a central role in the underpinnings of brain disease. Research in animal models supports that HDAC expression is a critical mediator of neural development, aging, cognition, learning and memory. Further, synthetic small molecules targeting HDACs have been shown to alleviate deficits in neural plasticity and disease-related behavior in animals underscoring the great need to improve understanding of the relationship between HDAC expression, brain function and disease pathogenesis. We have recently achieved a major research goal by resolving a PET imaging agent, [11C]Martinostat that selectively binds to a subset of HDAC enzymes. Our imaging studies to date, including in 7 healthy human volunteers, have identified key features that make [11C]Martinostat a rare and promising CNS HDAC probe including robust brain uptake and high specific binding. Using an AD mouse model, we have collected additional preliminary imaging data demonstrating increased tracer uptake - evidence of increased HDAC expression - in aged AD mice compared to age-matched healthy control animals, a result consistent with invasive protein measurements reported from postmortem human brain. We are extremely excited to take a large step forward in understanding cognitive decline by visualising HDAC in the healthy and dysfunctional human brain. Our lab in Martinos Center is one of few in the world that can directly translate basic science advancements to knowledge of the human system. Together with the our multidisciplinary teams and strong collaborations, we are seeking the support through the R21 mechanism for this high-risk, high-reward study to characterize the density and distribution of key HDACs throughout the brain of aging healthy subjects and in patients with Alzheimer's Disease. Our initial data on [11C]Martinostat in humans age 18-35 years strongly supports the success of our proposal for clinical imaging in healthy older subjects (Aim 1) and in AD patients (Aim 2). PET-MR imaging in humans with [11C]Martinostat will deliver answers to fundamental questions about chromatin modifying enzymes in the living human brain in a way that has not been possible until now. Importantly, using [11C]Martinostat to understand HDAC expression in AD, a profound example of cognitive decline and neurodegeneration, will enable validation of an epigenetic drug target, refine patient selection based on HDAC expression, and facilitate proof of mechanism/target engagement in novel therapeutic trials.

 描述（由适用提供）：组蛋白脱乙酰基酶（HDAC）酶是锌依赖性的染色质修饰蛋白，这些蛋白已成为理解CNS功能障碍的重要领导。迄今为止，已经在少数受脑部疾病影响的死后脑组织样本中测量了HDAC表达，包括精神分裂症，抑郁症和阿尔茨海默氏病（AD），并提供了在至少Cortex，Hippocampus和Hippocampus和Cerebellum中改变HDAC表达的证据，可能在脑中的中心症中起作用。动物模型中的研究支持HDAC表达是神经元发展，衰老，认知，学习和记忆的关键中介。此外，靶向HDAC的合成小分子已被证明可以减轻动物的神经元可塑性和与疾病相关的行为的定义，强调了提高对HDAC表达，大脑功能和疾病发病机理之间关系的理解的巨大需求。最近，我们通过解决宠物成像剂[11C] Martinostat实现了主要的研究目标，该宠物成像剂有选择地结合HDAC酶的子集。迄今为止，我们的成像研究，包括7名健康的人类志愿者，已经确定了使[11C] Martinostat成为罕见而有望的CNS HDAC探测器，包括强大的脑吸收和高特异性结合。与年龄匹配的健康对照动物相比，使用AD小鼠模型，我们收集了其他初步成像数据，表明示踪剂的吸收增加 - 较高的AD小鼠的HDAC表达的证据，这一结果与术后人类大脑报告的侵入性蛋白质测量结果一致。我们很高兴能通过可视化健康且功能障碍的人脑中的HDAC来迈出巨大的一步来理解认知能力下降。我们在马提尼斯中心（Martinos Center）的实验室是世界上少数几个可以直接翻译基础科学进步以了解人类系统的人之一。与我们的跨学科团队和强大的合作一起，我们通过R21机制寻求支持，对这项高风险，高回报的研究，以表征关键HDAC在整个衰老健康受试者和阿尔茨海默氏病患者中的密度和分布。我们对18-35岁人类的[11C] Martinostat的初步数据强烈支持我们在健康的老年受试者（AIM 1）和AD患者中对临床成像提出的成功（AIM 2）。 [11C] Martinostat在人类中的PET-MR成像将为有关染色质修饰的人类大脑中的酶的基本问题提供答案，直到现在到现在为止。重要的是，使用[11C] Martinostat了解AD中的HDAC表达，这是认知下降和神经退行性的一个深刻的例子，可以验证表观遗传药物靶标，基于HDAC表达的患者选择，并促进新型治疗试验中机制/靶标参与的证明。