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: 8960392
• 负责人: Kevin Haigis
• 金额: $ 7.86万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 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/8960392
• 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; Early Onset Familial Alzheimer' s Disease; 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; effective therapy; extracellular; 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.

描述（由申请人提供）：tau蛋白病是一组与年龄相关的神经退行性疾病，其特征是大脑特定区域出现神经原纤维缠结和其他Tau蛋白包涵体。这些病症是渐进性的、使人衰弱的，最终是致命的。每种 tau 蛋白病都有独特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情况下，并导致边缘和联合皮层变性，从而不影响邻近的运动和感觉区域。其他 tau蛋白病，包括额颞叶痴呆 (FTD)，都是脑叶变性。由于缺乏关于神经退行性疾病的解剖特异性和进展机制的分子机制的知识，对有效疗法的持续探索受到阻碍。我们在这项研究中的目标是通过查明神经退行性疾病发生和进展过程中大脑特定区域失调的信号通路来确定新的治疗靶点。我们识别这些途径的方法是开发 FTD 和 AD 小鼠模型大脑中细胞信号传导的定量、数据驱动的计算模型。我们从生物工程分析的角度提出的驱动假设是，神经变性与神经元多通路信号网络“状态”偏离正常有关，因此这种“状态”的扰动可以通过表征“网络表型”关系的计算模型预测的方式调节神经退行性疾病的发作和进展。需要计算模型来提供新颖的见解，这些见解无法通过对相关复杂数据集的直观检查轻易确定，从而了解控制神经元如何响应最终导致细胞死亡的损伤的关键途径的综合操作。重要的是，这种基于生物工程的观点也将有助于产生与通路扰动的表型效应相关的新的、多变量的推论假设。本质上，从神经变性小鼠模型生成的信号数据集衍生的计算模型将识别可以调节以控制疾病发作和进展的信号通路。