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; 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常见死亡风险 感染。由于从 老年人的SARS-COV-2感染。老年人在 疫苗接种，使它们容易受到常见的传染病。那是有必要改善的 免疫系统在古老的人中的功能，以降低感染率及其相关的感染率 负担。淋巴系统 - 淋巴结和淋巴管的持持态系统 - 弹奏着核心作用 产生免疫反应，取决于淋巴流以从病原体到淋巴结携带抗原 激活免疫细胞。我们和其他人已经表明，淋巴功能和淋巴流量降低 老年动物。降低的淋巴流量限制了抗原进入淋巴结并启动免疫 回复。那就是淋巴功能不良可能是导致免疫功能降低的潜在因素 在过去。老年小鼠淋巴功能降低的机制未充分表征。 此外，没有FDA批准的药物可以改善淋巴功能。总体目标 拟议的项目是定义驱动与衰老相关降低淋巴的机制 为了靶向这些机制以增强老年小鼠的淋巴和免疫功能。 淋巴肌肉细胞（LMC）是一种天然靶细胞，可以提高淋巴功能，因为它们驱动淋巴流动。 引起快速淋巴血管收缩。但是，LMC尚未得到很好的特征，并且经常 被认为是血管平滑肌细胞，在这些细胞类型的行为中拼命的明确表型差异。 在我们最近生成的LMC的转录组基础上，我们将比较LMC的转录组 在拟议的工作中，新鲜隔离的收集淋巴视频。这些数据将 确定靶向的机械途径，以增强老年动物的淋巴功能。此外，我们会的 确定转录变化是否取决于年龄相关的微环境差异。我们 还将测试通过不良免疫功能与衰老小鼠淋巴功能不良之间的因果关系 增加淋巴泵送药物。长期，我们将验证我们在人体组织中的发现和 开发治疗方法来增强老年人的淋巴功能。这项工作将构成 第一个FDA批准了改善淋巴功能的药物。我们新颖的治疗概念会导致更少 由于老年人的感染以及更好的疫苗效率而导致的住院和死亡，这将 预防常见病毒，例如影响力或SARS-COV-2，使老年人的死亡率驱动死亡率。这项工作 将由世界一流的淋巴管生物学专家团队进行，免疫学，单细胞RNASEQ 数据分析，内内淋巴流量测量和淋巴病患者的临床护理。