Neuropathological basis of brain network dysfunction

 描述（由申请人提供）：这是Salvatore Spina博士的K 08奖项申请，他是加州大学弗朗西斯科分校记忆与衰老中心的行为神经学研究员和临床讲师，他正在将自己确立为一名独立研究员，作为一名临床医生-科学家，专注于大脑网络功能障碍的神经病理学基质。该K 08奖项将为Spina博士提供必要的支持，以实现以下目标：（1）获得导致神经退行性变的分子和细胞机制方面的专业知识;（2）熟练使用结构和功能MRI方法;（3）获得使用切割的专业知识-通过使用创新的多重荧光平台，用于定量变性分子标志物的边缘方法;（4）获得蛋白质组学和蛋白质翻译后修饰质谱数据的重要性的经验，因为它们与神经变性有关;（5）提高他的生物统计学知识;（6）发展独立的研究生涯。为了实现这些目标，Spina博士组建了一个多学科的指导团队，主要导师是William塞利博士（一名行为神经学家，具有神经病理学和功能成像方面的专业知识）;两名共同导师：布鲁斯米勒医生（一位在行为，神经退行性疾病，和临床研究）和Lennart Mucke博士（一名神经学家和神经科学家，具有分子生物学和神经变性实验模型方面的专业知识）;和五名顾问：莱亚·格林伯格医生（神经病理学家，擅长选择性神经脆弱性和体视学神经病理学方法）; Eric Huang博士（神经病理学家，在神经发育和神经变性方面具有专长）; John Kornak博士（生物统计学家，擅长神经退行性疾病的统计分析）; Julie Schneider博士（一位神经病理学家，擅长脑老化和TDP-43蛋白质病）;和Judith Steen博士（一位在蛋白质组学、质谱和tau蛋白翻译后修饰方面具有专长的神经学家）。 该研究旨在探讨体内神经退行性变和神经元功能障碍的神经影像学标记物与疾病发病机制的死后分子标记物之间的关系。中心假设是脑网络脆弱性、成像变化和疾病表型表达是由tau蛋白病和TDP-43蛋白病中神经变性的选择性和不同的分子途径驱动的。我们将收集一组具有不同类型额颞叶变性综合征的受试者的影像学数据，并分析其与来自同一个体的尸检神经病理学标本中评估的神经病理学结果的相关性。我们将建立区域性脑萎缩或脑网络完整性降低与神经退行性变的半定量和定量测量之间的相关性（目标1）。我们将评估区域脑容量损失或受损的内在连接与通过多重荧光评估的大规模分子标记物的定量测量之间的相关性（目的2）。我们将探索tau蛋白病中tau蛋白翻译后修饰的特定特征与区域神经变性和网络功能障碍的成像测量之间的相关性，以及与疾病发病机制的分子标志物的定量测量之间的相关性（目的3）。这项研究将增加对神经变性和脑网络功能障碍的神经病理学基础的理解，指导未来的研究，以确定疾病治疗的新的潜在靶点，并提供有关使用神经影像学方法预测体内变性的特定分子机制的见解。K 08培训将使Spina博士能够将选择性脆弱性的概念应用于对神经退行性疾病的理解。

 DESCRIPTION (provided by applicant): This is a K08 award application for Dr. Salvatore Spina, a behavioral neurology fellow and clinical instructor at the University of California, San Francisco, Memory and Aging Center who is establishing himself as an independent investigator as a clinician-scientist focusing on neuropathological substrates of brain network dysfunction. This K08 award will provide Dr. Spina with the necessary support to accomplish the following: (1) gain expertise in molecular and cellular mechanisms leading to neurodegeneration; (2) develop proficiency in the use of structural and functional MRI methodologies; (3) gain expertise in the use of cutting-edge methodologies for quantification of molecular markers of degeneration by the use of an innovative multiplexed fluorescence platform; (4) gain experience on the significance of proteomics and mass-spectrometry data of protein post-translational modifications as they relate to neurodegeneration; (5) advance his knowledge of biostatistics; and (6) develop an independent research career. To achieve these goals, Dr. Spina has assembled a multidisciplinary mentoring team with primary mentor Dr. William Seeley (a behavioral neurologist with expertise in neuropathology and functional imaging); two co-mentors: Dr. Bruce Miller (a neurologist with expertise in behavior, neurodegenerative disease, and clinical research) and Dr. Lennart Mucke (a neurologist and neuroscientist with expertise in molecular biology and experimental models of neurodegeneration); and five advisors: Dr. Lea Grinberg (a neuropathologist with expertise on selective neuronal vulnerability and stereological neuropathological methodologies); Dr. Eric Huang (a neuropathologist with expertise in neurodevelopment and neurodegeneration); Dr. John Kornak (a biostatistician with expertise on statistical analysis of neurodegenerative diseases); Dr. Julie Schneider (a neuropathologist with expertise on brain aging and TDP-43 proteinopathies); and Dr. Judith Steen (a neurologist with expertise in proteomics, mass- spectrometry and tau-protein post-translational modifications). The proposed research investigates the relationship between in-vivo neuroimaging markers of neurodegeneration and neuronal dysfunction, and post-mortem molecular markers of disease pathogenesis. The central hypothesis is that brain network vulnerability, imaging changes, and disease phenotypic expression are driven by selective and distinct molecular pathways of neurodegeneration in tauopathies and TDP-43 proteinopathies. We will collect imaging data on a well-characterized cohort of subjects with diverse types of frontotemporal lobar degeneration syndromes and will analyze the correlations with neuropathological findings assessed in post-mortem neuropathological specimens from the same individuals. We will establish correlations between regional brain atrophy or reduced brain network integrity, and both semi-quantitative and quantitative measures of neurodegeneration (Aim 1). We will assess correlations between regional brain volume loss or impaired intrinsic connectivity and quantitative measures of a large scale of molecular markers as assessed by multiplexed fluorescence (Aim 2). We will explore correlations between specific profiles of tau protein post-translational modifications in tauopathies with imaging measures of regional neurodegeneration and network dysfunction, as well as with quantitative measures of molecular markers of disease pathogenesis (Aim 3). This research will increase the understanding of the neuropathological substrate of neurodegeneration and brain network dysfunction, direct future studies for the identification of new potential targets of disease treatment, and provide insights on the use of neuroimaging methodologies for the prediction of specific molecular mechanisms of degeneration in-vivo. This K08 training will enable Dr. Spina to apply concepts of selective vulnerability to the understanding of neurodegenerative diseases.