Molecular signature of parabiosis

联体共生的分子特征

基本信息

批准号：
10433951
负责人：
TONY WYSS-CORAY
金额：
$ 47.28万
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/10433951
关键词：
Adipose tissue Affect Age Aging Animal Model Atlases Biochemical Biochemical Pathway Biological Aging Blood Blood Circulation 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 bone repair cell type experience functional improvement healthspan human old age (65+)improved mitochondrial dysfunction muscle strength new therapeutic target normal aging novel novel therapeutics prevent programs proteostasis rational design 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.

项目概要衰老是全世界疾病和死亡的最大单一原因，通过靶向衰老可以使身体恢复活力因此，生物衰老过程有可能同时预防多种慢性疾病，例如癌症、心脏病、痴呆和糖尿病。虽然数十年的研究揭示了共同的特征衰老，如线粒体功能障碍、炎症和蛋白质稳态丧失，针对这些特征的治疗在动物模型中只引起了适度的恢复。这可能部分是因为大多数衰老研究都仅关注一种或几种器官或细胞类型，几乎没有时间分辨率，限制了我们的能力解释衰老如何以及何时影响这些互连的系统。不过最近我们尝试了对衰老进行如此系统的表征。使用批量 RNA 测序 (RNA-seq) 和单细胞 RNA- 对整个生命周期中的数十种小鼠器官和细胞类型（称为 Tabula Muris）进行测序 (scRNA-seq) Senis），我们发现了全身的整体和特定的衰老特征。但究竟如何，仍不得而知或者，如果，复兴范式影响这些全球衰老途径，或者更确切地说，煽动新生的生化程序。因此，新疗法的合理设计具有挑战性。一种对跨器官系统产生有益影响的复兴方法是异时性的联体共生，其中年轻和年老的小鼠共享共同的循环。表型如认知、肌肉通过接触年轻的血液，力量和骨骼修复都显示出功能的改善。联体共生研究主要集中在循环蛋白质与年龄相关的变化上，其中一些已经确定至少调节一些观察到的效应。然而，此类个别因素尚未实现稳健全身恢复活力，部分原因可能是由于对联体共生的影响不完全了解作用于不同的器官和细胞。使用我们新创建的 Tabula Muris Senis 数据来代表正常衰老，我们研究了联体共生后 3 种组织的 scRNA-seq 变化：性腺和肠系膜脂肪组织，其先于其他器官和肝脏经历与年龄相关的基因表达变化，因为肝细胞是其中之一第一种观察到受益于年轻循环系统的细胞类型。有趣的是，个人细胞类型对联体共生的反应差异很大，所有 3 种组织的血管内皮细胞均表现出与正常衰老基因一致的显着转录组变化。我们希望通过将此分析扩展到 9 种组织的 scRNA-seq 以及 21 种组织的批量 RNA-seq 组织中，我们可以发现特征，这些特征将作为识别具有强大功能的小分子的基础恢复活力和延长健康寿命。由于手术密集的联体共生受到细胞运输和同时暴露于年轻和年老的循环因子，我们进一步建议比较联体共生来自年轻血浆移植的特征，从而具体揭示了复兴的各个方面对血浆因子的变化敏感。与我们之前的数据集类似，所有数据都将公开。