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Molecular signature of parabiosis

联体共生的分子特征

基本信息

批准号：
10207226
负责人：
TONY WYSS-CORAY
金额：
$ 47.29万
依托单位：
STANFORD UNIVERSITY
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：
2021-07-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10207226
关键词：
Adipose tissue Affect Age Aging Animal Model Atlases Biochemical Biochemical Pathway Biological Aging Blood Blood Circulation Bone Regeneration Brain Cardiovascular system Cause of Death Cells Cessation of life Chronic Disease Cognition Data Data Set Dementia Diabetes Mellitus Disease Endothelial Cells Exhibits Exposure to Future Gene Expression Gene Expression Profile Generations Genetic Transcription Goals Health Heart Diseases Hepatocyte Human Individual Inflammation Injections Liver Longevity Malignant Neoplasms Mediating Mediator of activation protein Mesentery Methodology Methods Modeling Molecular Molecular Profiling Mus Ontology Operative Surgical Procedures Organ Organism Parabiosis Pathway interactions Pattern Phenotype Plasma Process Proteins Quality of life Rejuvenation Research Resistance Risk Factors Sampling Scientist System Testing Therapeutic Tissues Vascular Endothelial Cell Wild Type Mouse age effect age related aged aging gene base body system cell type design experience functional improvement healthspan human old age (65+)improved mitochondrial dysfunction muscle strength new therapeutic target normal aging novel novel therapeutics prevent programs proteostasis response single-cell RNA sequencing small molecule targeted treatment temporal measurement trafficking transcriptome transcriptome sequencing transcriptomics

项目摘要

PROJECT SUMMARY Aging is the single greatest cause of disease and death worldwide, and rejuvenating the body by targeting biological aging processes therefore holds potential to simultaneously prevent multiple chronic diseases like cancer, heart disease, dementia, and diabetes. While decades of research has unveiled common hallmarks of aging, like mitochondrial dysfunction, inflammation, and loss of proteostasis, therapies targeting these hallmarks have elicited only modest rejuvenation in animal models. This may be in part because most aging studies have focused on only one or a few organs or cell types, with little to no temporal resolution, limiting our ability to interpret how and when aging impacts these interconnected systems. Recently, however, we have attempted such a systematic characterization of aging. Using bulk RNA-sequencing (RNA-seq) and single-cell RNA- sequencing (scRNA-seq) on dozens of mouse organs and cell types across the lifespan (termed Tabula Muris Senis), we discovered global and specific aging signatures throughout the body. But it remains unknown how, or if, rejuvenation paradigms affect these global aging pathways, or rather instigate nascent biochemical programs. The rational design of new therapeutics is therefore challenging. One method of rejuvenation which has garnered beneficial effects across organ systems is heterochronic parabiosis, in which a young and old mouse share a common circulation. Phenotypes like cognition, muscle strength, and bone repair have all shown functional improvement through exposure to young blood. Parabiosis research has largely focused on age-related changes to circulating proteins, and several have been determined to mediate at least some of the observed effects. However, such individual factors have yet to achieve robust rejuvenation throughout the body, likely in part due to an incomplete understanding of the effects of parabiosis on disparate organs and cells. Using our newly created Tabula Muris Senis data to represent normal aging, we investigated scRNA-seq changes in 3 tissues following parabiosis: gonadal and mesenteric adipose tissues, which undergo age-related gene expression changes prior to other organs, and liver, as hepatocytes were one of the first cell types observed to benefit from exposure to a young circulatory system. Interestingly, individual cell types vary greatly in their response to parabiosis, with vascular endothelial cells from all 3 tissues showing prominent transcriptomic changes consistent with normal aging genes. It is our hope that by expanding this analysis to scRNA-seq of 9 tissues, and to bulk RNA-seq of 21 tissues, we can discover signatures that will serve as the basis for identifying small molecules capable of robust rejuvenation and healthspan extension. As surgically intensive parabiosis is confounded by cell trafficking and simultaneous exposure to young and aged circulating factors, we further propose to compare parabiosis signatures to those derived from young plasma transfer, thereby uncovering aspects of rejuvenation specifically sensitive to alterations in plasma factors. Similar to our earlier datasets, all data will be made publically available.

项目总结