Reversing aging-induced lymphatic dysfunction to improve immune function

逆转衰老引起的淋巴功能障碍，改善免疫功能

• 批准号: 10371505
• 负责人: TIMOTHY P PADERA
• 金额: $ 24.86万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10371505
• 关键词: 2019-nCoV; Age; Aging; Animals; Antibody Formation; Antigens; Atropine; Automobile Driving; Bacterial Infections; Biology; Blood Circulation; Blood Vessels; COVID-19 mortality; Calcium; Cardiac Myocytes; Cells; Cessation of life; Collecting Cell; Communicable Diseases; Dangerousness; Data; Data Analyses; Elderly; Elements; Epigenetic Process; FDA approved; Flu virus; Force of Gravity; Frequencies; Gene Expression Profile; Generations; Genetic Transcription; Goals; Heart; Hospitalization; Immune; Immune response; Immune system; Immunity; Immunologic Memory; Immunology; Impairment; In Vitro; Infection; Influenza; Lead; Lymphatic; Lymphatic Diseases; Lymphatic Endothelial Cells; Lymphatic System; Lymphatic function; Measurement; Measures; Mibefradil; Microscopy; Molecular; Mus; Muscle Cells; Muscle Contraction; Mycoses; Optics; Pathogenicity; Pathway interactions; Patient Care; Peripheral; Persons; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiologic pulse; Play; Pump; Role; SARS-CoV-2 infection; Skeletal Muscle; Smooth Muscle Myocytes; Structure of germinal center of lymph node; T-Cell Activation; Techniques; Testing; Tetrodotoxin; Therapeutic; Vaccination; Vascular Smooth Muscle; Virus; Virus Diseases; Work; adaptive immune response; age related; aged; antimicrobial; cell behavior; cell type; clinical care; comorbidity; differential expression; hospitalization rates; human tissue; immune function; immune system function; improved; improved functioning; in vivo; infection rate; lymph flow; lymph nodes; lymphatic dysfunction; lymphatic pump; lymphatic vessel; mortality; mortality risk; mouse model; novel therapeutics; pathogen; prevent; response; side effect; single-cell RNA sequencing; targeted treatment; tool; transcriptome; vaccine efficacy; young adult

One significant problem with aging is a reduced ability to generate immune responses to bacterial, viral and fungal infections, leading to more hospitalizations and putting elderly people at greater risk of death from common infections. This problem has been starkly demonstrated by the greater rates of hospitalization and death from SARS-CoV-2 infections in older people. Older people also have lower rates of generating immunity after vaccination, leaving them vulnerable to common infectious diseases. Thus, there is a need to improve the function of the immune system in elderly people in order to lower rates of infections and their associated burdens. The lymphatic system—consisting of lymph nodes and lymphatic vessels—plays a central role in generating immune responses, which depend on lymph flow to carry antigens from the pathogen to lymph nodes to activate immune cells. We, and others, have shown that lymphatic function and lymph flow are reduced in aged animals. The reduced lymph flow limits antigens from getting to lymph nodes and initiating an immune response. Thus, poor lymphatic function can be one potential factor that contributes to reduced immune function in the elderly. The mechanisms behind reduced lymphatic function in aged mice are not well characterized. Further, there are no FDA approved drugs indicated to improve lymphatic function. The overall goal of the proposed project is to define the mechanisms that drive the aging-related reduction in lymphatic function in order to target these mechanisms to boost both lymphatic and immune function in aged mice. Lymphatic muscle cells (LMCs) are a natural target cell to boost lymphatic function as they drive lymph flow by causing rapid lymphatic vessel contractions. LMCs however have not been well characterized and are often considered vascular smooth muscle cells, despite clear phenotypic differences in the behavior of these cell types. Building on our recently generated transcriptome of LMCs, we will compare the transcriptomes of LMCs from freshly isolated collecting lymphatic vessels from young and old mice in the proposed work. These data will identify mechanistic pathways to target in order to boost lymphatic function in aged animals. Further, we will determine whether the transcriptional changes are dictated by age-related microenvironmental differences. We will also test the causal relationship between poor immune function and poor lymphatic function in aged mice by increasing lymphatic pumping pharmacologically. Long-term, we will validate our findings in human tissue and develop therapeutic approaches to boost lymphatic function in elderly people. This work will form the basis for the first FDA approved drugs to improve lymphatic function. Our novel therapeutic concept would lead to fewer hospitalizations and deaths due to infections in elderly people as well as better vaccine efficacy, which will prevent common viruses, such as influenza or SARS-CoV-2, from driving mortality in elderly people. This work will be carried out by a world-class team of experts in lymphatic vessel biology, immunology, single cell RNAseq data analysis, intravital lymph flow measurements and clinical care of patients with lymphatic diseases.

衰老的一个重要问题是对细菌、病毒和 真菌感染导致更多的住院治疗，并使老年人面临更大的死于常见疾病的风险 感染。这一问题已经从更高的住院率和死亡率上得到了鲜明的证明。 SARS-CoV-2在老年人中的感染。老年人在死后产生免疫力的比率也较低 接种疫苗，使他们容易感染常见的传染病。因此，有必要改进 老年人免疫系统的功能，以降低感染率及其相关 负担。淋巴系统--由淋巴结和淋巴管组成--在 产生免疫反应，依靠淋巴流动将抗原从病原体带到淋巴结 来激活免疫细胞。我们和其他人已经证明，淋巴功能和淋巴流量在 年迈的动物。淋巴流量的减少限制了抗原进入淋巴结并启动免疫。 回应。因此，淋巴功能低下可能是导致免疫功能下降的一个潜在因素。 在老年人身上。老年小鼠淋巴功能降低的机制还没有得到很好的描述。 此外，没有FDA批准的药物表明可以改善淋巴功能。该计划的总体目标 拟议的项目是定义驱动与衰老相关的淋巴减少的机制 为了针对这些机制，提高老龄小鼠的淋巴和免疫功能。 淋巴肌肉细胞(LMC)是促进淋巴功能的天然靶细胞，因为它们通过 导致淋巴管快速收缩。然而，LMC还没有得到很好的表征，而且经常 被认为是血管平滑肌细胞，尽管这些细胞类型的行为有明显的表型差异。 在我们最近生成的LMC转录组的基础上，我们将比较来自 在拟议的工作中，新分离的收集幼年和老年小鼠的淋巴管。这些数据将 确定靶向的机械途径，以提高老年动物的淋巴功能。此外，我们还将 确定转录变化是否由年龄相关的微环境差异决定。我们 还将通过以下方式测试老年小鼠免疫功能低下和淋巴功能低下之间的因果关系 增加淋巴泵的药理作用。从长远来看，我们将在人体组织中验证我们的发现 开发提高老年人淋巴功能的治疗方法。这项工作将构成以下内容的基础 FDA第一次批准了改善淋巴功能的药物。我们的新治疗概念将导致更少 老年人因感染而住院和死亡，以及更好的疫苗效力，这将 防止常见病毒，如流感或SARS-CoV-2，导致老年人死亡。这部作品 将由世界一流的淋巴管生物学、免疫学、单细胞RNAseq专家团队进行 淋巴疾病患者的数据分析、活体淋巴流量测量和临床护理。