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

• 批准号: 10263387
• 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
• 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/10263387
• 关键词: Adult; Affect; Aging; Alzheimer' 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; 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; therapeutically effective; transcriptome sequencing; transcriptomics

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.

迟发性神经退行性疾病共同影响着700多万美国人 目前，医疗成本每年高达数千亿美元。认知能力下降是一种常见的特征 这些疾病中的许多，特别是阿尔茨海默氏症、帕金森氏症和血管性痴呆。在……里面 尽管在研究这些障碍方面取得了令人振奋的进展，但目前还没有可用的 能够改善认知的治疗学。因此，令人惊讶的是，来自 包括我们在内的一些实验室支持这样一种观点，即中枢神经系统受损后大脑功能的恢复可能 是可以实现的。许多数据来自对异型慢性寄生虫小鼠的研究--无论是年轻的还是年老的 循环系统已通过手术连接的小鼠。我们的其他研究也同样令人兴奋 他们证明，在老年小鼠体内注射单一因子GDF11，一种正常的血清蛋白，也是有效的 能够改善CNS的重要性能。具体地说，GDF11刺激神经发生，增加 神经活动和改善血管结构。令人惊讶的是，我们发现GDF11没有跨越血液- 而不是通过直接作用于老化的脑血管系统来发挥作用。这项建议 重点更详细地了解GDF11是如何对中枢神经系统产生这些改善作用的。 首先，我们将使用组织学、分子和转录学方法相结合的方法来研究其影响。 GDF11在更广泛的脑细胞上的作用。我们将采用包括神经标记物在内的几种方法 不同类型细胞的活性、神经发生、血管生成以及基因表达的变化，我们 将决定GDF11的S动作序列(检验GDF11的S神经效应是 间接和随之而来的对脑血管的影响)。接下来，我们将比较GDF11的S对小鼠肾细胞的作用。 CNS与其他转化生长因子β家族配体如GDF8、转化生长因子β2和修饰形式的GDF11的作用。 确定最有效的配体将有助于我们了解这些配体产生的分子变化，如 也为我们未来开发有效的治疗方法奠定了基础。最后，我们未发表的研究结果表明 GDF11及其信号通路的组成部分在多种脑细胞类型中表达 成人期。我们将比较和对比系统注射的GDF11和GDF11的功能 从大脑内部行动。我们将使用组织学和遗传扰动的组合来量化 GDF11及其受体在大脑不同区域的表达以及它们如何随着年龄的变化而改变。我们 然后将测量减少大脑GDF11对神经发生和神经功能的影响。这将是 更好地了解如果系统性GDF11直接接触到神经细胞可能会发生什么 血脑屏障受损的疾病。从这项工作中，我们希望获得一个 全面了解GDF11的作用，它们与其他转化生长因子β家族配体的关系， 以及通过使用这些因素可能对大脑功能有什么好处。