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(申请人提供)：组蛋白脱乙酰酶(HDAC)酶是锌依赖的染色质修饰蛋白，已成为了解中枢神经系统功能障碍的重要线索。到目前为止，已在少量死后脑组织样本中测量到HDAC的表达，这些脑组织样本来自受精神分裂症、抑郁症和阿尔茨海默病(AD)等脑部疾病影响的健康患者和疾病患者，并提供了证据，表明HDAC至少在皮质、海马体和小脑中的表达改变，可能在脑部疾病的基础上发挥核心作用。在动物模型中的研究支持HDAC的表达是神经发育、衰老、认知、学习和记忆的关键中介。此外，针对HDAC的合成小分子已被证明可以缓解动物神经可塑性和疾病相关行为的缺陷，这突显了提高对HDAC表达、脑功能和疾病发病机制之间关系的理解的迫切需要。我们最近通过解析一种PET显像剂[11C]Martinostat实现了一个主要的研究目标，它可以选择性地与HDAC酶的子集结合。到目前为止，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成为一种罕见且有前景的CNS HDAC探针的关键特征，包括强大的脑摄取和高特异性结合。使用AD小鼠模型，我们收集了额外的初步成像数据，显示与年龄匹配的健康对照组动物相比，老年AD小鼠的示踪剂摄取增加-HDAC表达增加的证据-这一结果与死后人脑报告的侵入性蛋白质测量结果一致。我们非常兴奋，通过在健康和功能失调的人脑中可视化HDAC，在理解认知衰退方面向前迈出了一大步。我们位于马蒂诺斯中心的实验室是世界上少数几个可以将基础科学进步直接转化为人类系统知识的实验室之一。与我们的多学科团队和强大的合作伙伴一起，我们正在通过R21机制为这项高风险、高回报的研究寻求支持，以表征关键HDAC在老年健康受试者和阿尔茨海默病患者大脑中的密度和分布。我们关于18-35岁人群中[11C]马替诺他汀的初步数据有力地支持了我们在健康的老年受试者(目标1)和AD患者(目标2)中进行临床成像的建议的成功。使用[11C]Martinostat在人类身上进行的PET-MR成像将以一种直到现在还不可能的方式，为活体人类大脑中染色质修饰酶的基本问题提供答案。重要的是，使用[11C]Martinostat了解AD中HDAC的表达，这是认知能力下降和神经退化的一个深刻例子，将使表观遗传药物靶点的验证成为可能，根据HDAC的表达改进患者选择，并有助于在新的治疗试验中证明机制/靶点参与。