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Role of early life hyperoxia on mesenchymal stem cell fate: their impact on age related disease

生命早期高氧对间充质干细胞命运的作用：它们对年龄相关疾病的影响

基本信息

批准号：
10312537
负责人：
Michael A O'Reilly
金额：
$ 23.1万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10312537
关键词：
5&apos -AMP-activated protein kinase Adipocytes Adult Affect Age Air Antioxidants Awareness Birth Bone Marrow Cardiac Myocytes Cardiovascular Diseases Cartoons Cell Proliferation Cell physiology Cells Chondrocytes Cyclic AMP-Dependent Protein Kinases Development Diastolic heart failure Disease Environmental Pollutants Exposure to Failure Fatty Acids Fatty acid glycerol esters Genetic Transcription Goals Grant Growth Harvest Health Heart Atrium Heart Diseases Homeostasis Human Hyperoxia Immune response Impairment Individual Influenza A virus Left Left atrial structure Life Lipids Longevity Lung Lung diseases Mesenchymal Differentiation Mesenchymal Stem Cells Modeling Mus Myofibroblast Neonatal Hyperoxic Injury Oxidation-Reduction Oxidative Stress Oxides Oxygen Pharmacology Phenotype Premature Birth Premature Infant Production Public Health Pulmonary veins Research Risk Risk Factors Role Source Superoxide Dismutase Testing Therapeutic Time Tissue Differentiation Toxic Environmental Substances Transgenic Organisms Viral Respiratory Tract Infection age related alveolar epithelium bone bone marrow mesenchymal stem cell donor stem cell extracellular fitness genetic approach improved influenza virus strain insight lipid biosynthesis mouse model neonatal infection novel therapeutics overexpression oxidation postnatal preservation prevent pulmonary function repaired stem cell fate stem cells stemness

项目摘要

PROJECT SUMMARY Exposure to environmental pollutants or toxins early in life can alter health and fitness as people age. Preterm infants are a prime example because their lungs are exposed too soon and often to excess amounts of oxygen at birth. These individuals are then at risk for growth failure, reduced lung function, impaired host response to respiratory viral infections, and development of cardiovascular disease as they age. We established a unique mouse model wherein exposure to high levels of oxygen (hyperoxia) at birth causes lung and heart disease later in life. Using this model, we now provide new evidence that neonatal hyperoxia also impairs growth by inhibiting fat accumulation. Bone marrow mesenchymal stem cells (BMSCs) isolated from these mice grew slower and were more oxidized. They also displayed reduced capacity to accumulate lipid and differentiate into adipocytes, possibly because they expressed higher levels of 5’-AMP activated protein kinase (AMPK), a master regulator of energy homeostasis that inhibits fatty acid synthesis and cell proliferation. Since the oxidation of stem cells increases with age, we will test the hypothesis that neonatal hyperoxia accelerates the oxidation of mesenchymal stem cells as mice age, thereby altering their ability to differentiate and produce fat. In Aim 1, we will determine how neonatal hyperoxia permanently reprograms the oxidation state and thus differentiation of bone, fat, and lung MSCs. Since growth failure is not seen when transgenic SftpcEC-SOD mice are exposed to hyperoxia, Aim 2 will determine if over-expression of the anti-oxidant extracellular superoxide dismutase by alveolar epithelial type 2 cells restores the oxidation state and adipogenic potential of MSCs. We will also determine whether EC-SOD preserves the differentiation of adjacent lipofibroblasts that support AT2 cell homeostasis. Impact on the Field: Understanding how neonatal hyperoxia disrupts adipogenesis is important because it will increase our understanding of how preterm birth alters health later in life.

项目总结