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Direct and Indirect Effects of GDF11 in the Aging Central Nervous System

GDF11 对衰老中枢神经系统的直接和间接影响

基本信息

批准号：
10206805
负责人：
Lee L Rubin
金额：
$ 62.59万
依托单位：
HARVARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10206805
关键词：
Adult Affect Aging Alzheimer&apos s Disease American Astrocytes Blood Blood - brain barrier anatomy Blood Vessels Brain Brain region Cardiovascular system Cell physiology Cells Cerebrovascular system Cognition Data Development Disease Family Future GDF11 gene GDF8 gene Gene Expression Genetic Genetic Transcription Health Health Care Costs Heterogeneity Hippocampus (Brain)Histologic Histology Impaired cognition In Vitro Injections Ligands Measures Methods Modification Molecular Mus Neuraxis Neurodegenerative Disorders Neuroglia Neurons Neurophysiology - biologic function Operative Surgical Procedures Parkinson Disease Positioning Attribute Production Property Publishing Recovery Serum Proteins Signal Pathway Signal Transduction Structure Testing Therapeutic Time Transcriptional Regulation Transforming Growth Factor beta Transgenic Mice Treatment Efficacy Vascular Dementia Vascular Endothelial Growth Factors Work adult neurogenesis aged aging brain angiogenesis base brain cell brain endothelial cell cell type experimental study improved nerve stem cell neurogenesis neuronal survival receptor relating to nervous system transcriptome sequencing transcriptomics

项目摘要

Late onset neurodegenerative diseases together affect more than 7 million Americans with associated healthcare costs currently reach hundreds of billions of dollars per year. Cognitive decline is a common feature of many of these diseases, especially Alzheimer’s disease, Parkinson’s disease, and vascular dementia. In spite of exciting progress being made in studying those disorders, currently, there are no available therapeutics capable of improving cognition. Therefore, it came as a surprise when a set of observations from a few labs, including ours, supported the notion that recovery of brain function after damage to the CNS might be achievable. Much of the data was obtained from studies of heterochronic parabiotic mice – young and old mice whose circulatory systems had been surgically joined. Our additional studies were equally exciting in that they demonstrated that injection of a single factor, GDF11, a normal serum protein, into aged mice was also able to improve important properties of the CNS. Specifically, GDF11 stimulated neurogenesis, increased neural activity and improved vascular structure. Surprisingly, we found that GDF11 does not cross the blood- brain barrier and instead may exert its effects by acting directly on aging brain vasculature. This proposal focuses on understanding in much greater detail how GDF11 exerts these ameliorative effects on the CNS. First, we will use a combination of histological, molecular and transcriptomic methods to investigate the effects of GDF11 on the cells of the brain more broadly. We will employ several measures including markers of neural activity, neurogenesis, angiogenesis, as well as changes in gene expression of the different cell types, and we will determine the sequence of GDF11’s actions (testing the hypothesis that GDF11’s neural effects are indirect and follow direct effects on brain vasculature). Next, we will compare GDF11’s effects on cells of the CNS with effects of other TGFβ-family ligands such as GDF8, TGFβ2 and modified forms of GDF11. Identifying the most effective ligand will help us understand the molecular changes these ligands produce, as well as position us to develop effective therapeutics in the future. Finally, our unpublished findings show that GDF11 and the components of its signaling pathway are expressed by multiple brain cell types well into adulthood. We will compare and contrast the functions of systemically injected GDF11 with those of GDF11 acting from within the brain. We will use a combination of histology and genetic perturbation to quantify the expression of GDF11 and its receptors across various regions the brain and how they are altered by aging. We will then measure the consequences of reducing brain GDF11 on neurogenesis and neural function. This will provide a better understanding of what might happen if systemic GDF11 gained direct access to neural cells in diseases in which the blood-brain barrier becomes compromised. From this work, we hope to gain a comprehensive understanding of the effects of GDF11, how they relate to those of other TGFβ-family ligands, and what benefits to brain function may be achieved by administering these factors.

晚发性神经退行性疾病总共影响了700多万美国人