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了超过 700 万美国人 目前，医疗保健费用每年达到数千亿美元。认知能力下降是一个普遍特征 其中许多疾病，尤其是阿尔茨海默病、帕金森病和血管性痴呆。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方法 能够改善认知的疗法。因此，当一系列观察结果出现时，人们感到惊讶。 包括我们在内的一些实验室支持这样的观点：中枢神经系统受损后大脑功能的恢复可能会 是可以实现的。大部分数据来自对异时性共生小鼠（年轻和年老）的研究 循环系统已通过手术连接的小鼠。我们的额外研究同样令人兴奋 他们证明，向老年小鼠注射单因子 GDF11（一种正常血清蛋白）也能起到作用。 能够改善中枢神经系统的重要特性。具体来说，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 不会穿过血液- 脑屏障，而是可能通过直接作用于老化的脑血管系统来发挥其作用。这个提议 重点是更详细地了解 GDF11 如何对 CNS 发挥这些改善作用。 首先，我们将结合组织学、分子和转录组学方法来研究其影响 GDF11 对大脑细胞的影响更广泛。我们将采用多种措施，包括神经标记物 活动、神经发生、血管发生以及不同细胞类型的基因表达的变化，我们 将确定 GDF11 的动作顺序（检验 GDF11 的神经效应是的假设 对脑血管系统的间接影响和直接影响）。接下来，我们将比较GDF11对细胞的影响 CNS 受其他 TGFβ 家族配体（例如 GDF8、TGFβ2 和 GDF11 的修饰形式）的影响。 识别最有效的配体将帮助我们了解这些配体产生的分子变化，如 并使我们能够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 GDF11 及其信号通路的组成部分由多种脑细胞类型表达 成年期。我们将系统注射GDF11与GDF11的功能进行比较和对比 从大脑内部起作用。我们将结合组织学和遗传扰动来量化 GDF11 及其受体在大脑各个区域的表达以及它们如何因衰老而改变。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 更好地了解如果系统性 GDF11 直接接触神经细胞会发生什么 血脑屏障受损的疾病。通过这项工作，我们希望获得 全面了解 GDF11 的作用，以及它们与其他 TGFβ 家族配体的关系如何， 通过管理这些因素可以给大脑功能带来哪些好处。

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.