Identifying Pathophysiological Signatures of DLB Cognitive and Neuropsychiatric Decline Using a Systems-Based Proteomic Approach

使用基于系统的蛋白质组学方法识别 DLB 认知和神经精神下降的病理生理学特征

• 批准号: 10579233
• 负责人: Lenora Higginbotham
• 金额: $ 19.52万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579233
• 关键词: Alzheimer' s Disease; Alzheimer' s disease brain; Amygdaloid structure; Anti-Anxiety Agents; Antipsychotic Agents; Area; Automobile Driving; Autopsy; Binding; Biochemical; Bioinformatics; Biological Markers; Biological Process; Biology; Brain; Cerebral cortex; Cerebrospinal Fluid; Cerebrospinal Fluid Proteins; Cholinesterase Inhibitors; Clinical; Clinical Management; Co-Immunoprecipitations; Cognitive; Competence; Complex; Data; Data Set; Dementia with Lewy Bodies; Deposition; Deterioration; Diffuse; Disease; Endothelium; Functional disorder; Funding; Goals; Impaired cognition; Individual; Laboratories; Link; Maps; Mass Spectrum Analysis; Measures; Mentors; Mentorship; Metabolic; Metabolic Pathway; Metabolism; Molecular; Molecular Profiling; Monitor; Nerve Degeneration; Neurobehavioral Manifestations; Neurologist; Neurons; Observational Study; Parkinsonian Disorders; Pathogenesis; Pathologic; Pathology; Pathway Analysis; Pathway interactions; Physicians; Pilot Projects; Precipitation; Preparation; Procedures; Process; Productivity; Protein Analysis; Proteins; Proteome; Proteomics; Psychoses; Reproducibility; Research; Resources; Sampling; Scientist; Symptoms; System; Techniques; Temporal Lobe; Therapeutic; Tissues; Training; Validation; Western Blotting; Work; affective disturbance; alpha synuclein; biobank; brain based; comparison control; disabling symptom; effective therapy; experimental study; frontal lobe; innovation; link protein; motor disorder; neuropsychiatry; non-motor symptom; novel; novel marker; partial response; psychiatric symptom; stem; synuclein; synucleinopathy; treatment response

Project Summary / Abstract Dr. Higginbotham is a promising physician-scientist who aspires to unravel the molecular pathophysiology underlying the cognitive and neuropsychiatric decline of Dementia with Lewy bodies (DLB) and identify novel protein signatures that help monitor and treat these debilitating symptoms. This K23 will advance her goals by providing training and mentorship in the following core competencies: 1) bioinformatics; 2) molecular proteomic techniques; and 3) clinical observational research. Dr. Higginbotham has assembled a mentoring team with unparalleled expertise in these areas and their applications to neurodegeneration research. Her primary mentor, Dr. Allan Levey, is a world-renowned cognitive neurologist who leads a highly productive laboratory with basic and translational expertise in Alzheimer's disease (AD) research. Her co-mentor, Dr. Nicholas Seyfried, is an expert in mass spectrometry (MS)-based proteomics and Director of the Emory Integrated Proteomics Core. She will also work closely with a host of collaborators who will provide key biospecimen and analytical resources. This project will use a systems-based proteomics approach to globally profile the corticolimbic pathophysiology of DLB and identify protein signatures of this dysfunction in cerebrospinal fluid (CSF). The rationale for these experiments stems from a staggering lack of biomarkers that assist in the monitoring and treatment of DLB cognitive and neuropsychiatric decline. While synuclein accumulation in corticolimbic regions correlates strongly to these devastating non-motor symptoms, little is known regarding the complex molecular processes surrounding this pathology. Therefore, efforts to better define the corticolimbic pathophysiology of DLB promise to not only enhance our scientific understanding of disease, but also promote the discovery of novel molecular signatures that advance the clinical management of its cognitive and neuropsychiatric decline. Dr. Higginbotham has spent the last two years optimizing brain-CSF integrative proteomic strategies in AD. This work resulted in the identification of novel CSF AD protein signatures linked to a diverse range of cortical pathophysiology. These exciting analyses comprise much of the pilot data for this proposal and will serve as a template for its experiments in DLB. In Aim 1, Dr. Higginbotham will apply co- expression network analysis to the DLB corticolimbic proteome to identify key disease-associated pathways. She will then use co-immunoprecipitation MS to examine pathological synuclein interactors in disease. In Aim 3, she will measure protein signatures of this brain-based pathophysiology in DLB CSF. Based on preliminary data, Dr. Higginbotham hypothesizes that the cortical and limbic regions of the DLB brain feature altered protein pathways and synuclein interactors involved in cellular metabolism. She also expects this corticolimbic pathophysiology to manifest in the CSF as unique DLB protein signatures that could advance our ability to monitor and treat its cognitive and neuropsychiatric decline. This work will prepare Dr. Higginbotham to compete for R01 funding in novel mechanistic and biomarker research in DLB and related parkinsonian disorders.

项目总结/摘要 博士希金波坦是一个有前途的物理学家，科学家谁渴望解开分子病理生理学 潜在的认知和神经精神衰退的路易体痴呆症（DLB），并确定新的 蛋白质特征有助于监测和治疗这些使人衰弱的症状。K23将通过以下方式实现其目标： 提供以下核心能力的培训和指导：1）生物信息学; 2）分子蛋白质组学 技术; 3）临床观察研究。希金波坦博士组建了一个指导小组 在这些领域及其在神经变性研究中的应用方面具有无与伦比的专业知识。她的主要导师， 博士Allan Levey是世界著名的认知神经学家，他领导着一个高效的实验室， 阿尔茨海默病（AD）研究的专业知识和翻译。她的共同导师尼古拉斯·塞弗里德博士是一位 基于质谱（MS）的蛋白质组学专家，埃默里综合蛋白质组学核心主任。她 还将与许多合作者密切合作，这些合作者将提供关键的生物标本和分析资源。 该项目将使用基于系统的蛋白质组学方法， 研究DLB的病理生理学并鉴定脑脊液（CSF）中这种功能障碍的蛋白质特征。 这些实验的基本原理源于惊人的缺乏生物标志物，有助于监测和 治疗DLB认知和神经精神衰退。当突触核蛋白在皮质边缘区域聚集时， 与这些毁灭性的非运动症状密切相关，关于复杂的分子 围绕这个病理过程。因此，更好地定义皮质边缘病理生理学的努力 DLB的承诺不仅提高了我们对疾病的科学认识，而且还促进了 发现新的分子特征，推进其认知和 神经精神衰退希金波坦博士在过去的两年里一直在优化脑CSF整合 AD中的蛋白质组学策略这项工作导致鉴定了新的CSF AD蛋白特征， 各种各样的皮质病理生理学这些令人兴奋的分析包括了大部分的试点数据， 建议，并将作为其在DLB实验的模板。在目标1中，希金波坦博士将申请共同- 表达网络分析的DLB皮质边缘蛋白质组，以确定关键的疾病相关的途径。 然后，她将使用免疫共沉淀MS来检查疾病中的病理性突触核蛋白相互作用。在目标3中， 她将在DLB CSF中测量这种基于脑的病理生理学的蛋白质特征。根据初步数据， 博士Higginbotham假设DLB大脑的皮质和边缘区域的特征是蛋白质改变， 途径和突触核蛋白相互作用参与细胞代谢。她还希望大脑皮层边缘 病理生理学在CSF中表现为独特的DLB蛋白特征，可以提高我们的能力， 监测和治疗其认知和神经精神衰退。这项工作将帮助希金波坦博士 用于DLB和相关帕金森病的新型机制和生物标志物研究的R 01资金。