Direct Visualization of Cell-Type Specific AD Networks for Drug Development

用于药物开发的细胞类型特异性 AD 网络的直接可视化

基本信息

批准号：
8712022
负责人：
Jin Hyung Lee
金额：
$ 182.76万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-15 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8712022
关键词：
Adverse effects Affect Alzheimer&apos s Disease Animal Behavior Animal Disease Models Animals Area Behavioral Biological Assay Brain Cells Clinical Clinical Trials Data Development Disease Disease Progression Dose Drug Design Drug Evaluation Elements Functional Magnetic Resonance Imaging Future Genetic Identity Hippocampus (Brain)Human Imagery Imaging technology Impairment In Vitro Individual Life Location Methodology Modeling Monitor Mus Neocortex Nervous system structure Neurologic Neurons Output Pathway interactions Pattern Pharmaceutical Preparations Pharmacotherapy Phase I Clinical Trials Phenotype Physiological Population Prevention Process Publishing Resolution Rest Scanning Signal Transduction Specific qualifier value Staging Surrogate Markers System Technology Testing Therapeutic Effect Time Translations awake basal forebrain basal forebrain cholinergic neurons base behavior test cell type cholinergic cholinergic neuron clinical efficacy cost disease phenotype drug candidate drug development drug efficacy in vivo mutant nervous system disorder neural circuit neuronal cell body new technology normal aging novel optogenetics pre-clinical public health relevance relating to nervous system response

项目摘要

DESCRIPTION (provided by applicant): An important challenge in drug development for Alzheimer's Disease (AD), as well as many other neurological diseases, is the accurate pre-clinical predictability of the future clinical efficacy and side effects of the compound. The complexity of the neurological system makes it extremely difficult to infer impact of the candidate compound using surrogate in vitro information, ex vivo data, or simple animal behavior models. Our proposal aims to fundamentally transform this process through accurate disease circuit characterization along with in vivo full brain quantification of the drug administration impact longitudinally over time in the same animals utilizing the optogenetic functional magnetic resonance imaging (ofMRI) technology. ofMRI is a novel technology combining cell type specific, temporally precise optogenetic control with fMRI readouts. The first proof of concept study published by the PI demonstrated ofMRI technology's ability to accurately visualize brain-wide neural activity resulting from cell types specified by its genetic identity, cell body location, and axonal projection target. With further developments in ofMRI technology to achieve high-throughput, high spatial resolution, and awake scanning, the PI's lab has preliminary data showing the ability to characterize whole brain network response specifically associated with basal forebrain cholinergic neurons. Selective stimulation of cholinergic neurons in the basal forebrain with defined temporal patterns was shown to elicit widespread neural activity including the hippocampus and neocortex. Such direct functional visualization of the network activity with the ability to longitudinally track in vivo can be used o characterize the disease progress, actively identify novel target circuits, and also monitor how different doses and course of treatment impacts each individual animal over time with disease progress. This is in contrast with conventional ex vivo technology that relies on sacrificing a large number of animals at different time points, which increases variance, cost, and time while only obtaining passive, surrogate markers of function or difficult to reproduce behavioral tests. I this proposal, we will quantify network function across normal, and mutant APP mice to quantify network function changes associated with cholinergic neurons of the basal forebrain. With these quantifications, we aim to establish this approach as a new platform for quantitative drug design and evaluation. With the ability to observe network engagement associated with key neural circuit elements implicated in AD, we will identify the AD circuit mechanism and also test a candidate drug that has already shown good electrophysiological, behavioral, and anatomical efficacy. We aim to demonstrate ofMRI-based observation of therapeutic effects. The prevention and/or reversal of AD-related circuit impairment could be fully or partially effective and we will e able to directly observe locations of the changes associated with specific neuronal populations in live animal brains during disease progression and drug therapy. Resting state fMRI studies will also be conducted in parallel to increase translational potential into clinical settings.

描述（由申请人提供）：阿尔茨海默氏病（AD）药物开发的重要挑战以及许多其他神经系统疾病，是该化合物的未来临床疗效和副作用的准确临床前可预测性。神经系统的复杂性使使用体外信息，离体数据或简单的动物行为模型来推断候选化合物的影响非常困难。我们的建议旨在通过准确的疾病电路表征来从根本上转变这一过程，并在同一动物中使用光遗传学功能磁共振成像（OFMRI）技术在同一动物中对药物的体内进行全脑量化。 OFMRI是一项新型技术，将特异性，时间精确的光遗传学控制与fMRI读数相结合。 PI发表的第一个概念研究证明了MRI技术能够准确可视化由细胞类型所产生的脑范围的神经活动，其遗传认同，细胞体位置和轴突投射目标。随着OFMRI技术的进一步发展，以实现高通量，高空间分辨率和清醒扫描，PI的实验室具有初步数据，表明能够表征与基础前脑胆碱能神经元特别相关的整个大脑网络响应的能力。具有定义的时间模式的基础前脑中胆碱能神经元的选择性刺激显示出广泛的神经活动，包括海马和新皮层。可以使用纵向跟踪体内的能力的网络活动的直接功能可视化o特征是疾病进展，积极识别新的目标电路，并监测不同剂量和治疗方法如何随着时间的推移影响每个动物随着疾病进展的影响。这与常规的离体技术相反，该技术依赖于在不同时间点牺牲大量动物的情况，这增加了差异，成本和时间，而仅获得被动的，功能的替代标记或难以再现行为测试。我的建议，我们将量化跨正常和突变的应用小鼠的网络函数，以量化与基础前脑的胆碱能神经元相关的网络功能变化。通过这些量化，我们旨在将这种方法建立为定量药物设计和评估的新平台。有了观察与与AD有关的关键神经电路元件相关的网络参与的能力，我们将确定AD电路机制，并测试已经显示出良好的电生理，行为和解剖学疗效的候选药物。我们旨在证明基于MRI的治疗作用的观察。与广告相关的电路损伤的预防和/或逆转可能是完全或部分有效的，我们将能够直接观察到疾病进展和药物治疗期间活动物大脑中与特定神经元种群相关的变化的位置。还将同时进行静止状态fMRI研究，以增加转化潜力到临床环境。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（1）

A guide to using functional magnetic resonance imaging to study Alzheimer's disease in animal models.

DOI：
10.1242/dmm.031724
发表时间：
2018-05-18
期刊：
Disease models & mechanisms
影响因子：
4.3
作者：
Asaad M;Lee JH
通讯作者：
Lee JH

Whole-brain microscopy reveals distinct temporal and spatial efficacy of anti-Aβ therapies.

DOI：
10.15252/emmm.202216789
发表时间：
2023-01-11
期刊：
EMBO MOLECULAR MEDICINE
影响因子：
11.1
作者：
Kirschenbaum, Daniel;Dadgar-Kiani, Ehsan;Catto, Francesca;Voigt, Fabian F.;Trevisan, Chiara;Bichsel, Oliver;Shirani, Hamid;Nilsson, K. Peter R.;Frontzek, Karl J.;Paganetti, Paolo;Helmchen, Fritjof;Lee, Jin Hyung;Aguzzi, Adriano
通讯作者：
Aguzzi, Adriano

Thalamic Input to Orbitofrontal Cortex Drives Brain-wide, Frequency-Dependent Inhibition Mediated by GABA and Zona Incerta.