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: 10661530
• 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/10661530
• 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; Cell secretion; Cells; Central Nervous System; Cerebrovascular system; Cognition; Data; Development; Disease; Elderly; Family; Future; GDF11 gene; GDF8 gene; Gene Expression; Genetic; Genetic Transcription; Health; Health Care Costs; Heterogeneity; Hippocampus; Histologic; Histology; Impaired cognition; In Vitro; Injections; Ligands; Measures; Methods; Modification; Molecular; Mus; 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; Transcriptional Regulation; Transforming Growth Factor beta; Transgenic Mice; Vascular Dementia; Vascular Endothelial Growth Factors; Work; adult neurogenesis; aged; aging brain; angiogenesis; brain cell; brain endothelial cell; cell type; experimental study; improved; nerve stem cell; neural; neurogenesis; neuronal survival; receptor; therapeutically effective; transcriptome sequencing; transcriptomics; young adult

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.

延迟发作神经退行性疾病共同影响超过700万的美国人 目前，医疗保健费用每年达到数亿美元。认知下降是一个共同的特征 其中许多疾病，尤其是阿尔茨海默氏病，帕金森氏病和血管性痴呆。 在研究这些疾病时取得了令人兴奋的进步，目前尚无可用 能够改善认知的治疗剂。因此，当一套来自 一些实验室，包括我们的实验室，支持了以下观点，即损害中枢神经系统后大脑功能的恢复可能 成功。大部分数据是从异chronic parabiotic小鼠的研究中获得的 电路系统已通过手术加入的小鼠。我们的其他研究同样令人兴奋 他们证明，将单个因子GDF11（正常血清蛋白）注射到老年小鼠中也是 可以改善中枢神经系统的重要特性。具体而言，GDF11刺激了神经发生，增加了 神经活动和改善的血管结构。令人惊讶的是，我们发现GDF11没有跨过血液 大脑屏障，而是通过直接对衰老的脑脉管系统作用来执行其影响。这个建议 重点详细了解GDF11如何对CNS执行这些改善影响。 首先，我们将使用组织学，分子和转录组方法的组合来研究效果 大脑细胞上的GDF11的范围更广泛。我们将采取多种措施，包括神经标记 活性，神经发生，血管生成以及不同细胞类型的基因表达的变化，我们 将确定GDF11动作的顺序（检验GDF11神经效应的假设是 间接并遵循对脑脉管系统的直接影响）。接下来，我们将比较GDF11对细胞的影响 CNS具有其他TGFβ家族配体的影响，例如GDF8，TGFβ2和GDF11的改良形式。 确定最有效的配体将帮助我们了解这些配体产生的分子变化，因为 以及我们将来开发有效疗法的定位。最后，我们未发表的发现表明 GDF11及其信号通路的组件通过多种脑细胞类型表达 成年。我们将比较和对比系统注射的GDF11的功能与GDF11的功能 从大脑内部表现。我们将结合组织学和遗传扰动来量化 GDF11及其在各个区域的接收器的表达以及大脑如何通过衰老改变它们。我们 然后，将测量减少脑GDF11对神经发生和神经功能的后果。这会 提供更好地了解如果系统性GDF11在直接访问神经细胞中可能发生的情况 血脑屏障被损害的疾病。通过这项工作，我们希望获得 全面了解GDF11的影响，它们与其他TGFβ家族配体的影响如何 通过管理这些因素，可以实现大脑功能的好处。