Immune and inflammatory system changes in SuperAgers

超级老年人的免疫和炎症系统变化

• 批准号: 10687274
• 负责人: Matt Huentelman
• 金额: $ 34.52万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10687274
• 关键词: Acute; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease risk; Anterior; Antibodies; Autoimmune Diseases; B-Cell Antigen Receptor; B-cell receptor repertoire sequencing; Brain; Cells; Cessation of life; Characteristics; Cognition; Cognition Disorders; Cognitive; DNA Sequence; Databases; Disease; Elderly; Exhibits; Freezing; Frequencies; Gene Expression Profile; General Population; Genes; Genetic Variation; Health; Human Genetics; Immune; Immune response; Immune system; Immunogenetics; Impaired cognition; Individual; Infection; Infectious Agent; Inflammation; Inflammatory; Inflammatory Response; Link; Longevity; Measurement; Measures; Memory; Microglia; Middle frontal gyrus structure; Molecular; Neurodegenerative Disorders; Organ; Organism; Participant; Pathway interactions; Peripheral; Phenotype; Plasma; Play; Process; Research Design; Resistance; Role; Sampling; Stress; System; T cell receptor repertoire sequencing; T-Lymphocyte; Variant; Viral; Work; age related; age related cognitive change; brain health; brain tissue; cell type; cingulate cortex; cognitive capacity; cohort; comparison control; cytokine; cytokine release syndrome; design; disorder risk; entorhinal cortex; genetic risk factor; genetic variant; neuroprotection; peer; resilience; response; single nucleus RNA-sequencing; targeted sequencing; trait; transcriptome

ABSTRACT (Project 2) Immune and inflammatory system functions are important to respond to infection, however, emerging evidence suggests that alterations in these systems accompany normative aging and neurodegenerative disease changes (like Alzheimer's disease, AD). Less deeply understood is the constitutive impact of these systems on organs and cells throughout the life span. In the proposed work we will explore the potential impact of immune and inflammatory processes on the brain and the influence of these processes on resistance and resilience to age-related cognitive changes that contribute to SuperAging. The basis for this approach is the well documented immune and inflammatory system changes noted in normative aging, the pro-inflammatory microglial changes associated with aging and AD, and the emergence of well-validated genetic risk factors for AD that have demonstrated the importance of immune and inflammatory system genes in risk for the disease. These findings suggest the immune and inflammatory system may play both a role in acute responses to infection as well as exert a long-term impact on brain health, age-related cognitive changes, and/or resilience to brain-related diseases. Project 2 of the SuperAging Consortium will explore this question through the study of unique individuals within the general population who exhibit the phenotype of cognitive SuperAging – a trait defined as a two- decade, or greater, superiority of memory capacity when compared to age-matched peers. We propose that immune and inflammatory system function is related to the cognitive resilience seen in SuperAging individuals – in the opposing way that it is related to risk for AD. We hypothesize that SuperAgers (SA) will demonstrate a shift toward neuroprotection and lower pro-inflammatory profiles compared to Control and AD participants and that these differences will clarify mechanisms of resilience to age-related phenomena. These hypotheses will be pursued through three aims. In Aim 1 we will profile the individual transcriptomes of microglia and other cells in brain tissue from SAs, Controls, and AD participants. In Aim 2 we will examine three different measures of the adaptive immune and inflammatory systems – cytokine levels, T- and B-cell receptor repertoires, and antibody profiles – in peripheral samples from SAs, Controls, and AD participants. Lastly, in Aim 3, we will investigate the DNA sequence variations in ~500 different immune and inflammatory system genes in SAs and Controls. This study design will allow us to unravel the link between potentially modifiable immune and inflammatory processes and resistance to age-related decline of cognitive capacity.

摘要（项目2） 免疫和炎症系统功能对于对感染的反应很重要，但是出现了 证据表明，这些系统的改变涉及正常衰老和神经退行性疾病 变化（如阿尔茨海默氏病，AD）。这些系统对 器官和细胞在整个生命周期中。在拟议的工作中，我们将探讨免疫的潜在影响 以及对大脑的炎症过程以及这些过程对抵抗和弹性的影响 与年龄相关的认知变化有助于超级传播。这种方法的基础是有据可查的 免疫和炎症系统在正常衰老中指出，促炎小胶质细胞变化 与衰老和AD相关，以及已充分验证的AD遗传危险因素的出现 证明了免疫和炎症系统基因在疾病风险中的重要性。这些发现 建议免疫系统和炎症系统可能在感染的急性反应中起作用 对大脑健康，与年龄相关的认知变化和/或对与大脑有关的弹性产生长期影响 疾病。 超级联盟的项目2将通过研究独特的个体来探讨这个问题 在一般人群中，揭露了认知超衰老的表型 - 一种定义为两个的特征 与年龄匹配的同龄人相比，十年或更高的记忆能力优势。我们提出了这一点 免疫和炎症系统功能与超级个体中看到的认知韧性有关 - 以与AD风险有关的相反方式。我们假设Superagers（SA）将证明 与对照和广告参与者相比 这些差异将阐明与年龄相关现象的韧性机制。这些假设将是 通过三个目标追求。在AIM 1中，我们将介绍小胶质细胞和其他细胞的单个转录组 来自SAS，对照和AD参与者的脑组织。在AIM 2中，我们将研究三种不同的措施 自适应免疫和炎症系统 - 细胞因子水平，T和B细胞受体曲目以及抗体 轮廓 - 在来自SAS，对照和广告参与者的外围样品中。最后，在AIM 3中，我们将调查 SAS和对照中的〜500种不同免疫和炎症系统基因的DNA序列变化。这 研究设计将使我们能够揭开潜在可修改的免疫和炎症过程之间的联系 并抵抗与年龄相关的认知能力下降。