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

 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，已成为了解CNS功能障碍的重要线索。迄今为止，已经在来自受脑病症（包括精神分裂症、抑郁症和阿尔茨海默病（AD））影响的健康和患病患者的少量死后脑组织样品中测量了HDAC表达，并且提供了HDAC在至少皮质、海马和小脑中的改变的表达可能在脑疾病的基础中起核心作用的证据。动物模型的研究支持HDAC表达是神经发育、衰老、认知、学习和记忆的关键介质。此外，靶向HDAC的合成小分子已经显示出减轻动物中神经可塑性和疾病相关行为的缺陷，这强调了对改善HDAC表达、脑功能和疾病发病机制之间关系的理解的巨大需求。我们最近通过解析PET显像剂[11 C] Martinostat实现了一个主要的研究目标，该显像剂选择性地结合HDAC酶的一个子集。我们迄今为止的成像研究，包括7名健康人类志愿者，已经确定了使[11 C] Martinostat成为罕见且有前途的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，我们已经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小鼠中示踪剂摄取增加-HDAC表达增加的证据，这一结果与尸检人脑中报告的侵入性蛋白质测量结果一致。我们非常高兴能够通过在健康和功能失调的人类大脑中可视化HDAC，在理解认知衰退方面迈出一大步。我们在Martinos中心的实验室是世界上为数不多的可以直接将基础科学进步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有力的合作一起，我们正在通过R21机制寻求对这项高风险，高回报研究的支持，以表征衰老健康受试者和阿尔茨海默病患者大脑中关键HDAC的密度和分布。我们在18 - 35岁人群中获得的[11C] Martinostat的初步数据强烈支持我们在健康老年受试者（目标1）和AD患者（目标2）中临床成像的成功建议。使用[11 C] Martinostat进行人体PET-MR成像将以一种迄今为止尚不可能的方式回答有关活体人脑中染色质修饰酶的基本问题。重要的是，使用[11 C] Martinostat来了解AD中的HDAC表达，这是认知衰退和神经退行性变的一个深刻例子，将能够验证表观遗传药物靶标，基于HDAC表达来完善患者选择，并促进在新的治疗试验中证明机制/靶标参与。

 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.