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、病毒和细菌产生免疫反应的能力下降。 真菌感染，导致更多的住院治疗，老年人因常见疾病死亡的风险更大 感染的住院率和死亡率的上升清楚地证明了这个问题。 老年人感染 SARS-CoV-2 后产生免疫力的率也较低。 疫苗接种，使他们容易感染常见传染病，因此有必要改进疫苗接种。 老年人免疫系统的功能，以降低感染率及其相关 淋巴系统（由淋巴结和淋巴管组成）在负担中发挥着核心作用。 产生免疫反应，这依赖于淋巴流将抗原从病原体携带到淋巴结 我们和其他人已经证明，淋巴功能和淋巴流量会减少。 老年动物的淋巴流量减少限制了抗原进入淋巴结并启动免疫。 因此，淋巴功能不良可能是导致免疫功能下降的潜在因素之一。 老年小鼠淋巴功能下降的机制尚不清楚。 此外，FDA 还没有批准任何药物可以改善淋巴功能。 拟议的项目是确定驱动衰老相关淋巴管减少的机制 功能，以针对这些机制来增强老年小鼠的淋巴和免疫功能。 淋巴肌细胞 (LMC) 是增强淋巴功能的天然靶细胞，因为它们通过以下方式驱动淋巴液流动： 然而，LMC 尚未得到很好的表征，并且经常被 尽管这些细胞类型的行为存在明显的表型差异，但仍被认为是血管平滑肌细胞。 基于我们最近生成的 LMC 转录组，我们将比较来自 这些数据将在拟议的工作中从年轻和年老的小鼠中新鲜分离收集淋巴管。 此外，我们将确定目标的机制途径，以增强老年动物的淋巴功能。 确定转录变化是否由年龄相关的微环境差异决定。 还将测试老年小鼠免疫功能差和淋巴功能差之间的因果关系 从长远来看，我们将在人体组织和中验证我们的发现。 开发增强老年人淋巴功能的治疗方法。这项工作将成为以下研究的基础。 第一个 FDA 批准的改善淋巴功能的药物将导致更少。 老年人因感染而住院和死亡以及更好的疫苗功效，这将 这项工作旨在预防流感或 SARS-CoV-2 等常见病毒导致老年人死亡。 将由淋巴管生物学、免疫学、单细胞RNAseq领域的世界级专家团队进行 数据分析、活体淋巴流量测量以及淋巴疾病患者的临床护理。