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（由申请人提供）：组蛋白脱乙酰酶（HDAC）是锌依赖性染色质修饰蛋白，已成为理解中枢神经系统功能障碍的重要线索迄今为止，已在少量死后脑组织样本中测量了 HDAC 表达。研究人员对受精神分裂症、抑郁症和阿尔茨海默病 (AD) 等脑部疾病影响的健康和患病患者进行了研究，并提供了至少在皮质、海马体和大脑皮层中 HDAC 表达发生改变的证据。动物模型研究表明，HDAC 表达是神经发育、衰老、认知、学习和记忆的关键介质。此外，针对 HDAC 的合成小分子已被证明可以缓解这种疾病。动物神经可塑性和疾病相关行为的缺陷强调了提高对 HDAC 表达、大脑功能和疾病发病机制之间关系的理解的迫切需要。我们最近通过解决 PET 成像剂实现了一个主要研究目标， [11C]Martinostat 选择性结合 HDAC 酶的子集，迄今为止，我们的成像研究（包括 7 名健康人类志愿者）已经确定了使 [11C]Martinostat 成为稀有且有前途的 CNS HDAC 探针的关键特征，包括强大的大脑摄取和高水平。使用 AD 小鼠模型，我们收集了额外的初步成像数据，证明与年龄匹配的健康对照动物相比，老年 AD 小鼠示踪剂摄取增加（HDAC 表达增加的证据），该结果与侵入性蛋白测量结果一致。我们非常高兴能够通过可视化健康和功能失调的人脑中的 HDAC 来了解认知衰退，我们的实验室是世界上少数几个能够直接转化基础科学进展的实验室之一。与我们的多学科团队和强有力的合作一起，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，以表征整个大脑中衰老过程中关键 HDAC 的密度和分布。健康受试者和我们在 18-35 岁人群中使用 [11C]Martinostat 的初步数据有力地支持了我们在健康老年受试者（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 对人体进行成像将以一种迄今为止无法实现的方式解答有关活人大脑中染色质修饰酶的基本问题。 [11C]Martinostat 了解 AD 中的 HDAC 表达（认知衰退和神经退行性疾病的深刻例子）将能够验证表观遗传药物靶点，根据 HDAC 表达完善患者选择，并促进新治疗试验中机制/靶点参与的证明。