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

迟发性神经退行性疾病共同影响超过700万美国人， 医疗保健费用目前达到每年数千亿美元。认知能力下降是一个共同的特征 许多这些疾病，特别是阿尔茨海默氏病，帕金森氏病和血管性痴呆。在 尽管在研究这些疾病方面取得了令人兴奋的进展，但目前还没有可用的 能够改善认知的治疗剂。因此，当一组来自 一些实验室，包括我们的实验室，支持这样的观点，即中枢神经系统受损后的脑功能恢复可能会导致神经系统的损伤。 可以实现。大部分数据来自异时联体小鼠的研究--年轻的和年老的 通过手术连接循环系统的小鼠。我们的其他研究同样令人兴奋， 他们证明，向老年小鼠注射单一因子GDF 11（一种正常血清蛋白）， 能够改善CNS的重要特性。具体而言，GDF 11刺激神经发生，增加 神经活性和改善的血管结构。令人惊讶的是，我们发现GDF 11不会穿过血液- 脑屏障，而是可以通过直接作用于老化的脑血管系统来发挥其作用。这项建议 重点是更详细地了解GDF 11如何对CNS发挥这些改善作用。 首先，我们将使用组织学，分子和转录组学方法的组合来研究影响 GDF 11对大脑细胞的影响。我们将采用几种措施，包括神经标记物， 活性、神经发生、血管生成以及不同细胞类型的基因表达变化，我们 将决定GDF 11的行动顺序（测试GDF 11的神经效应是 对脑血管系统间接和随后的直接影响）。接下来，我们将比较GDF 11对细胞的作用， CNS与其他TGFβ家族配体（如GDF 8、TGFβ2和GDF 11的修饰形式）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， 并使我们在未来开发有效的治疗方法。最后，我们未发表的研究结果表明， GDF 11及其信号通路的组分由多种脑细胞类型表达， 成年我们将比较和对比全身注射的GDF 11与GDF 11的功能 从大脑内部运作。我们将使用组织学和遗传扰动的组合来量化 GDF 11及其受体在大脑不同区域的表达以及它们如何被衰老改变。我们 然后将测量减少大脑GDF 11对神经发生和神经功能的影响。这将 更好地理解如果系统性GDF 11直接进入神经细胞， 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GDF 11的作用，它们如何与其他TGFβ家族配体的作用相关， 以及通过施用这些因子可以实现对大脑功能的益处。

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.