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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

基本信息

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
项目类别：
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

项目摘要

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.

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.