In vivo systems biology of neurodegenerative diseases

神经退行性疾病的体内系统生物学

• 批准号: 8163405
• 负责人: Kevin Haigis
• 金额: $ 36.11万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8163405
• 关键词: Affect; Alzheimer' s Disease; American; Amyloid; Amyloid beta-Protein Precursor; Amyloid deposition; Animals; Appearance; Automobile Driving; Biomedical Engineering; Brain; Brain region; Cell Death; Cessation of life; Characteristics; Clinical; Complex; Computer Simulation; Data; Data Set; Deposition; Development; Disease; Disease Progression; Emerging Technologies; Etiology; Exhibits; Foundations; Frontotemporal Dementia; Genetic; Gliosis; Goals; Human; Inflammation; Knowledge; Lobar; Modeling; Molecular; Motor; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Onset of illness; Pathway interactions; Patients; Pattern; Phenotype; Population; Resistance; Sensory; Signal Pathway; Signal Transduction; Specificity; Stimulus; Synapses; Systems Biology; Tauopathies; Testing; Therapeutic Intervention; Transgenic Animals; Transgenic Mice; Variant; age related; association cortex; base; computational network modeling; design; early onset; effective therapy; extracellular; familial Alzheimer disease; functional disability; genetic analysis; in vivo; insight; mouse model; mutant; neuron loss; new therapeutic target; novel; novel therapeutics; operation; presenilin-1; research study; tau Proteins; tau mutation; therapeutic target

DESCRIPTION (provided by applicant): The tauopathies are a diverse group of age-related neurodegenerative diseases that are characterized by the development of neurofibrillary tangles and other Tau inclusions in specific regions of the brain. These conditions are progressive and debilitating, and are ultimately fatal. Each tauopathy has distinct clinical and morphologic features, but all have the characteristic of affecting unique neuronal populations. In Alzheimer's Disease (AD), which affects over 5 million Americans, the tauopathy occurs in the setting of amyloid depositions and causes degeneration of limbic and association cortices, sparing adjacent motor and sensory regions. Other tauopathies, including frontotemporal dementia (FTD), are lobar degenerations. The continuing search for effective therapies is crippled by the lack of knowledge pertaining to the molecular mechanisms underlying the anatomical specificity and mechanisms of progression of neurodegenerative disease. Our goal in this study is to identify novel therapeutic targets by pinpointing those signaling pathways that are dysregulated in specific regions of the brain during the onset and progression of neurodegeneration. Our approach to identifying these pathways is to develop quantitative, data-driven computational models of cellular signaling in the brains of mouse models of FTD and AD. Our driving hypothesis, arising from a bioengineering analysis perspective, is that neuro-degeneration is associated with a deviation of the neuronal multi-pathway signaling network 'state' from normal, such that perturbation of this 'state' can modulate the onset and progression of neurodegenerative disease in ways predictable from a computational model characterizing the "network-phenotype" relationship. Computational modeling is required to provide novel insights, not readily ascertained from intuitive inspection of the associated complex data-sets, into the integrative operation of key pathways that govern how neurons respond to the insults that ultimately result in cell death. Importantly, this bioengineering-based perspective will also help to generate new, multi-variate corollary hypotheses relating to the phenotypic effects of pathway perturbation. In essence, the computational models derived from signaling datasets generated from mouse models of neurodegeneration will identify signaling pathways that can be modulated to control disease onset and progression. PUBLIC HEALTH RELEVANCE: The tauopathies are a diverse group of incurable age-related neurodegenerative diseases that affect millions of Americans. Our study aims to utilize emerging technologies and computational modeling to characterize the molecular and cellular changes that occur in the brain during the onset and progression of tau-related neurodegenerative disease. Our ultimate goal is to identify new therapeutic opportunities to protect neurons from the ravaging effects of the pro-death stimuli that underlie neurodegeneration.

描述（由申请人提供）：tau蛋白病是一组不同的年龄相关神经退行性疾病，其特征在于在脑的特定区域中发展神经元缠结和其他Tau内含物。这些情况是渐进的和衰弱的，最终是致命的。每种tau蛋白病具有不同的临床和形态学特征，但都具有影响独特神经元群体的特征。在影响超过500万美国人的阿尔茨海默病（AD）中，tau蛋白病发生在淀粉样蛋白沉积的背景下，并引起边缘和联合皮质的变性，从而保留相邻的运动和感觉区域。其他tau蛋白病，包括额颞叶痴呆（FTD），是脑叶变性。对有效疗法的持续研究由于缺乏与神经退行性疾病的解剖学特异性和进展机制相关的分子机制有关的知识而受到阻碍。我们在这项研究中的目标是确定新的治疗目标，通过精确定位那些信号通路，在神经变性的发病和进展过程中，在大脑的特定区域失调。我们识别这些途径的方法是在FTD和AD小鼠模型的大脑中开发定量的、数据驱动的细胞信号传导计算模型。我们的驱动假说，从生物工程分析的角度来看，是神经退行性变与神经元多通路信号网络的“状态”从正常的偏差，这样的扰动，这种“状态”可以调节神经退行性疾病的发病和进展的方式可预测的计算模型表征的“网络表型”的关系。计算建模需要提供新的见解，不容易确定从相关的复杂数据集的直观检查，到关键通路的整合操作，控制神经元如何响应最终导致细胞死亡的损伤。重要的是，这种基于生物工程的观点也将有助于产生新的，多变量的推论假说有关的途径扰动的表型效应。从本质上讲，从神经变性小鼠模型生成的信号数据集导出的计算模型将识别可以被调节以控制疾病发作和进展的信号通路。 公共卫生相关性：tau蛋白病是一组不同的无法治愈的与年龄相关的神经退行性疾病，影响数百万美国人。我们的研究旨在利用新兴技术和计算建模来表征tau相关神经退行性疾病发作和进展期间大脑中发生的分子和细胞变化。我们的最终目标是确定新的治疗机会，以保护神经元免受导致神经变性的促死亡刺激的破坏作用。