Proj 2 - Lymphatic system as a conduit for age-related defective proteostasis in AD

Proj 2 - 淋巴系统作为 AD 中与年龄相关的蛋白质稳态缺陷的管道

• 批准号: 10602559
• 负责人: LAURA SANTAMBROGIO
• 金额: $ 39.14万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10602559
• 关键词: Active Immunotherapy; Address; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Antigens; Autoantigens; Autophagocytosis; Awareness; Biochemical; Blood; Brain; Brain Drains; Brain Pathology; Cells; Cellular biology; Cervical; Cervical lymph node group; Clinical Trials; Communication; Complex; Data; Degenerative Disorder; Dendritic Cells; Development; Disease; Endosomes; Event; Geroscience; Goals; Immune; Immune System Diseases; Immune response; Immune system; Immunologic Surveillance; Immunotherapy; Inflammation; Inflammatory; Lymph; Lymphatic System; Maps; Mediating; Modification; Molecular; Molecular Profiling; Mus; Nerve Degeneration; Organ; Organelles; Oxidation-Reduction; Passive Immunotherapy; Pathologic; Pathology; Pathway interactions; Peptide Mapping; Peptides; Peripheral; Phase; Phenotype; Physiological; Play; Post Translational Modification Analysis; Post-Translational Protein Processing; Process; Proteins; Proteome; Proteomics; Role; Stains; System; T cell response; T-Lymphocyte; Testing; Therapeutic; Trust; Vaccination; Weather; adaptive immune response; age related; aging brain; biophysical analysis; brain parenchyma; humanized mouse; lymphatic circulation; mouse model; protein aggregation; proteostasis; synthetic peptide

Summary A pro-inflammatory signature accompanied by changes in cellular proteostasis are observed in brain neurodegenerative conditions such as AD and to less extent in the aging brain. However, despite the great advancement towards the understanding of the connection between inflammation, AD development and aging-related pathologies, there are several important aspects, which are still very much under investigated. For example albeit it is appreciate the existence of the lymphatic system, as a brain-to-periphery communication conduit, it is still unknown the role played by the lymph in the inflammatory/degenerative process occurring in the brain parenchyma and in transporting the brain molecular signature to the cervical nodes for immune-surveillance. Another important aspect, yet to be investigated, are the very early changes in endosomal proteostasis and the proteome post-translational modifications, occurring before bona fide AD and aging degenerative changes are observed. Finally, despite the fact that active and passive immunotherapy has been proposed for AD the role of MHCII-restricted immune response to naturally processed TAU, Aβ and other brain self-antigens is still unknown. As such the trust of this application is to: (i) explore the role played by the lymphatic circulation in transporting the inflammatory/degenerative molecular signature of the brain parenchyma to the draining cervical node (with P1 and Core B) (ii) map the very early changes in the brain proteome, PTM- modifications, endo-lysosomal proteostasis and autophagic machinery (with P1 and Core C) (iii) analyze changes in the MHC II-restricted immune-peptidome, and related T cell responses, during aging and the different phases of AD progression (with P3 and Core B). By using state-of the art quantitative proteomic, associated with a cell biology approach, we will map proteins PTMs at different stages of the aging process and AD development as well as their effect on endo-lysosomal proteostasis and the autophagic machinery. Additionally we will investigate the lymph inflammatory/degenerative signature in young and old mice, as well as, AD mice at different stage of disease. Finally, the MHC II-immunopeptidome, eluted from dendritic cells in the cervical node, will be analyzed by MS/MS to map peptides derived from brain-relevant proteins in aging and at different stages of AD. Tetramer staining, using relevant MHC-II-peptides, will be employed to analyze T cell recognition and address the overall immune responses to brain antigens. Altogether results from this project will provide a progressive snap shot of how the cellular proteome is modified during the early-to-late stages of AD or aging development, how the autophagic machinery is involved in disposing the modified proteome, how these early changes progressively develop into complex aggregates and how the endo-lysosomal system is involved in restoring proteostasis. Additionally, how the lymphatic system function as a conduit to transport the inflammatory/degenerative phenotype associated with AD development to the immune system and conversely how immune cells respond to proteomic changes in aging and during AD progression.

摘要在细胞蛋白抑制剂的变化中实现了促炎的特征。 大脑神经退行性疾病，例如AD和衰老大脑的程度较小。但是，dospite 迈向理解创新，广告发展与 与衰老有关的病理，有几个重要方面，这些方面仍未对其进行研究。 例如，尽管如此，它是淋巴系统的存在，作为脑对外周期的存在 通讯导管，淋巴在炎症/退化中所起的作用仍然未知 发生在脑实质中并在将脑分子特征转运到宫颈的过程中发生的过程 免疫监视的节点。另一个重要方面，尚待调查，是早期的变化 内体蛋白质抑制剂和蛋白质组后翻译后修饰，发生在真正的AD和 观察到老化的退化性变化。最后，使主动和被动免疫疗法具有的事实 我们被提出了AD的MHCII限制性免疫响应对自然加工的TAU，Aβ和其他的作用 脑自我抗原仍然未知。因此，此应用程序的信任是：（i）探索 淋巴圆转运大脑的炎症/退化分子特征 实质到排水宫颈节点（带有P1和Core B）（ii）映射大脑的早期变化 蛋白质组，PTM-修饰，内溶剂体蛋白抑制剂和自噬机械（带有P1和Core C） （iii）分析在衰老期间，分析MHC II限制的免疫肽组和相关T细胞反应的变化 以及AD进展的不同阶段（使用P3和Core B）。通过使用最新技术定量 与细胞生物学方法相关的蛋白质组学，我们将在衰老的不同阶段绘制蛋白质PTM 过程和广告开发以及它们对内溶性蛋白质的影响和自噬 机械。此外，我们将研究年轻人和老年人的淋巴炎性/退化性特征 小鼠以及AD小鼠处于不同疾病的不同阶段。最后，MHC II-免疫肽组，从 宫颈节点中的树突状细胞将通过MS/MS分析以绘制源自大脑相关的胡椒体 衰老和AD不同阶段的蛋白质。使用相关MHC-II肽的四聚体染色将是 用于分析T细胞识别并解决对脑抗原的总体免疫回应。 该项目的总共结果将提供一个渐进的快照，以了解细胞蛋白质组的方式 在广告或衰老开发的早期阶段进行了修改，如何涉及自噬机械 在处理修改的蛋白质组时，这些早期变化如何逐步发展为复杂的聚集体 以及内聚糖体系统如何恢复蛋白质量。另外，淋巴样 系统功能是运输与AD相关的炎症/退化表型的管道 对免疫系统的开发，相反，免疫细胞如何应对衰老的蛋白质组学变化 以及在AD进展过程中。