Proteomic Discovery in Parkinson-Dementia Complex of Guam

关岛帕金森痴呆症的蛋白质组学发现

• 批准号: 7235848
• 负责人: Thomas J Montine
• 金额: $ 15.99万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7235848
• 关键词: Abbreviations; Alzheimer' s Disease; Amyloid; Amyotrophic Lateral Sclerosis; Antibodies; Biological Models; Brain; Brain region; Cerebellar cortex structure; Characteristics; Complex; Data; Detergents; Disease; Elderly; Electrospray Ionization; Environmental Risk Factor; Enzyme-Linked Immunosorbent Assay; Evaluation; Exploratory/Developmental Grant; Formic Acids; Fostering; Freezing; Future; Genetic; Genetic Predisposition to Disease; Genetic Screening; Genomics; Guam; Hippocampus (Brain); Immunohistochemistry; Indigenous; Indium; Lasers; Localized; Mariana Islands; Mass Spectrum Analysis; Midbrain structure; Middle frontal gyrus structure; Minor; Minority Groups; Molecular; Neostriatum; Neurodegenerative Disorders; Neurofibrillary Tangles; Parkinson Disease; Parkinson' s Dementia; Parkinson-dementia complex of Guam; Pathogenesis; Pathologic; Patients; Peptides; Phenotype; Pontine structure; Progressive Supranuclear Palsy; Proteins; Proteomics; Public Health; Relative (related person); Research; Resources; Series; Spectrometry; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Standards of Weights and Measures; Structure of middle temporal gyrus; Tauopathies; Techniques; Technology; Testing; Therapeutic; Thinking; Time; Tissues; United States National Institutes of Health; abnormally phosphorylated tau; base; environmental stressor; ethnic minority population; formic acid; insight; ionization; member; novel; research study; synuclein; tau Proteins; tool

DESCRIPTION (provided by applicant): Parkinson-dementia complex (PDC) of the Chamorros on Guam and surrounding Mariana Islands is a unique neurodegenerative disease that remains a significant public health burden to the older members of this indigenous ethnic minority. Current data indicate that PDC is a complex phenotype that likely derives significant contributions from advancing age, inherited susceptibilities, and as yet to be clarified environmental factors. This complex phenotype represents a severe challenge to standard genomic and epidemiologic approaches to identifying key pathogenic elements in PDC. Identification of detergent-insoluble (DI) protein has provided keen insight into the molecular pathogenesis of other complex neurodegenerative diseases like Alzheimer's disease. Here we will test the hypothesis that discovering and quantifying DI proteins specific to PDC will provide much needed new perspective on this enigmatic disease and perhaps other neurodegenerative diseases. We will test our hypothesis through specific aims that employ novel discovery tools focused at the protein level so as to have the capacity to capture pathologic changes from either genetic or environmental influences. We will: (i) discover and quantify relative amounts of DI protein specific to PDC using LC-MALDI-TOF-TOF with isobaric tagging for relative and absolute protein quantification, (ii) confirm and validate results using a series of antibody-based techniques, and (iii) localize validated proteins in tissue sections from patients with PDC, other tauopathies, and appropriate controls. Once complete, data from these experiments will provide a fresh and unique perspective on new elements in the pathogenesis of PDC and thereby serve to focus future genetic screens, searches for environmental influences, and evaluation of experimental therapeutics in model systems.

描述（由申请人提供）：关岛及其周围马里亚纳群岛查莫罗人的帕金森-痴呆综合症（PDC）是一种独特的神经退行性疾病，仍然是这一土著少数民族老年人的重大公共卫生负担。目前的数据表明，PDC是一种复杂的表型，可能与年龄增长、遗传易感性和尚未明确的环境因素有关。这种复杂的表型对确定PDC关键致病因素的标准基因组学和流行病学方法提出了严峻的挑战。洗涤剂不溶性（DI）蛋白的鉴定为其他复杂神经退行性疾病如阿尔茨海默病的分子发病机制提供了敏锐的洞察力。在这里，我们将测试发现和量化PDC特异性DI蛋白的假设，将为这种神秘疾病和其他神经退行性疾病提供急需的新视角。我们将通过使用专注于蛋白质水平的新发现工具的特定目标来测试我们的假设，以便有能力从遗传或环境影响中捕获病理变化。我们将：(i)使用LC-MALDI-TOF-TOF发现和量化PDC特异性DI蛋白的相对数量，并使用等压标记进行相对和绝对蛋白质定量，（ii）使用一系列基于抗体的技术确认和验证结果，以及（iii）在PDC患者、其他牛头病变患者和适当对照的组织切片中定位经过验证的蛋白质。一旦完成，这些实验的数据将为PDC发病机制的新因素提供一个全新而独特的视角，从而为未来的基因筛选、环境影响的研究和模型系统中实验治疗方法的评估提供重点。