Neuropathological basis of brain network dysfunction

 描述(由申请者提供)：这是一份K08奖项申请书，申请者是塞尔瓦托·斯皮纳博士，他是加州大学旧金山分校记忆和衰老中心的行为神经学研究员和临床讲师，正在将自己确立为一名独立的研究员，作为一名临床医生和科学家，专注于大脑网络功能障碍的神经病理基础。此次K08奖项将为Spina博士提供必要的支持，以完成下列任务：(1)获得导致神经退行性变的分子和细胞机制的专业知识；(2)熟练使用结构和功能磁共振方法；(3)获得通过使用创新的多路荧光平台量化退行性变分子标记的尖端方法方面的专业知识；(4)获得蛋白质组学和质谱学数据的重要意义，因为它们与神经退行性变相关；(5)增进他在生物统计学方面的知识；以及(6)发展独立的研究事业。为了实现这些目标，Spina博士组建了一个多学科导师团队，包括主要导师William Seeley博士(在神经病理学和功能成像方面有专长的行为神经学家)、两位共同导师：Bruce Miller博士(在行为、神经退行性疾病和临床研究方面有专长)和Lennart Mucke博士(神经学家和神经科学家，在分子生物学和神经变性实验模型方面有专长)；以及五位顾问：Lea Grinberg博士(在选择性神经元脆弱性和立体神经病理学方法方面有专长的神经病理学家)；Eric Huang博士(在神经发育和神经变性方面有专长的神经病理学家)；John Kornak博士(擅长神经退行性疾病统计分析的生物统计学家)、Julie Schneider博士(擅长脑老化和TDP-43蛋白疾病的神经病理学家)和Judith Steen博士(擅长蛋白质组学、质谱学和tau蛋白翻译后修饰)。这项拟议的研究调查了神经变性和神经元功能障碍的体内神经成像标记物和疾病发病机制的死后分子标记物之间的关系。中心假设是大脑网络脆弱性、成像变化和疾病表型表达是由tauopsis和TDP-43蛋白病中选择性和独特的神经退行性变的分子通路驱动的。我们将收集一组不同类型的额颞叶变性综合征受试者的影像数据，并将其与同一个体的尸检神经病理标本评估的神经病理结果的相关性进行分析。我们将建立局部脑萎缩或脑网络完整性降低与神经变性的半定量和定量测量之间的相关性(目标1)。我们将评估区域脑体积丢失或受损的内在连接性与通过多重荧光评估的大规模分子标记的定量测量之间的相关性(目标2)。我们将探索tau蛋白翻译后修饰的特定特征与局部神经变性和网络功能障碍的成像指标以及疾病发病机制的分子标记物的定量指标之间的相关性(目标3)。这项研究将增加对神经退行性变和脑网络功能障碍的神经病理基础的了解，指导未来的研究，以确定新的潜在疾病治疗靶点，并为使用神经成像方法预测体内退行性变的特定分子机制提供见解。这次K08培训将使Spina博士能够将选择性易损性的概念应用到对神经退行性疾病的理解上。

 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.