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: 10371714
• 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/10371714
• 关键词: Alzheimer' s Disease; Alzheimer' s disease brain; Amygdaloid structure; Anti-Anxiety Agents; Antipsychotic Agents; Area; Automobile Driving; Autopsy; Base of the Brain; 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; 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; base; biobank; delta protein; 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.

项目摘要/摘要 希金波坦博士是一位有前途的内科科学家，他渴望揭开分子病理生理学的面纱。 路易体痴呆的认知和神经精神衰退的基础(DLB)和识别新 帮助监测和治疗这些衰弱症状的蛋白质信号。这位K23将把她的目标推进到 提供以下核心能力方面的培训和指导：1)生物信息学；2)分子蛋白质组学 技术；3)临床观察性研究。希金波坦博士组建了一个指导团队， 在这些领域及其在神经变性研究中的应用方面的无与伦比的专业知识。她的主要导师， 艾伦·利维博士是一位世界知名的认知神经学家，他领导着一个高效的实验室， 以及阿尔茨海默病(AD)研究方面的翻译专业知识。她的联合导师尼古拉斯·塞弗里德博士是一位 他是基于质谱仪(MS)的蛋白质组学专家，也是Emory集成蛋白质组学核心的主管。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样品和分析资源。 这个项目将使用一种基于系统的蛋白质组学方法来全局描述皮质边缘 并在脑脊液(CSF)中确定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地缺乏帮助监测和 治疗DLB认知和神经精神衰退。而皮质边缘区域的突触核蛋白积聚 与这些毁灭性的非运动症状密切相关，对这种复杂的分子知之甚少 围绕这一病理过程。因此，更好地定义皮质边缘病理生理学的努力 承诺不仅加强我们对疾病的科学认识，而且还将促进 发现新的分子标记，促进其认知和治疗的临床治疗 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-脑脊液的整合 阿尔茨海默病的蛋白质组策略。这项工作导致了新的脑脊液AD蛋白信号的鉴定 不同范围的皮质病理生理学。这些令人兴奋的分析包含了这方面的大部分试点数据 建议，并将作为其在德意志银行进行试验的模板。在目标1中，希金波坦博士将联合 表达网络分析，以DLB皮质边缘蛋白质组，以确定关键的疾病相关途径。 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脑脊液中测量这种基于大脑的病理生理学的蛋白质特征。根据初步数据， 希金波坦博士假设DLB大脑的皮质和边缘区域的蛋白质发生了变化 参与细胞新陈代谢的通路和突触核蛋白相互作用因子。她还期待着这种皮质边缘 病理生理学在脑脊液中表现为独特的DLB蛋白信号，可以提高我们的能力 监测和治疗其认知和神经精神衰退。这项工作将为希金波坦博士参加比赛做好准备 为R01提供资金，用于DLB和相关帕金森病的新机制和生物标记物研究。