Baboon model of chemotherapy-related cognitive impairment and accelerated aging

项目摘要 化疗是一种非常有效的癌症治疗方法；然而，除了化疗的好处外， 有许多不良后果，包括化疗相关的认知障碍(CRCI)和 加速衰老。尽管对生活质量有影响，但这些领域的研究相对较少，而且有 目前没有FDA批准的治疗方法可用。一个复杂的动物模型将解决这个问题 对于我们对长期后果的理解和对发展 潜在的治疗方法。目前，CRCI和化疗相关的加速衰老在啮齿动物中进行了研究，但一种 非人灵长类动物模型将显著提高解决这一仍未得到充分研究的研究的有效性 现象。在这项拟议的研究中，我们的目标是建立一种恒河猴慢性脑梗塞和加速衰老的模型。我们 将在狒狒样本中进一步定义健康老龄化，然后调查化疗是否会诱导认知 像在人类身上一样，减少和加速狒狒的大脑衰老，并测试一种干预措施，这种干预已经被 对小鼠有效。我们将收集狒狒的脑成像、认知和衰老分子生物标记物数据 在仅用顺铂或顺铂加HDAC6抑制剂治疗之前。然后我们将进一步收集 治疗后的脑、认知和衰老数据，以检查与化疗方案和 HDAC6抑制剂是否能逆转认知衰退和神经退化。这些数据将用于 提出进一步的研究和技术，以潜在地减轻化疗的这些后果 人类。

Project Summary Chemotherapy is an extremely effective treatment for cancer; however, along with chemotherapy’s benefits there are many undesirable consequences including chemotherapy-related cognitive impairments (CRCI) and accelerated aging. Despite impacts on quality of life, these areas are relatively understudied and there are currently no FDA approved treatments available. A sophisticated animal model to address this problem will be extremely valuable, both to our understanding of the long-term consequences and to the development of potential treatments. Currently, CRCI and chemotherapy-related accelerated aging is studied in rodents, but a nonhuman primate model will significantly enhance the validity of studies addressing this still under-researched phenomenon. In this proposed study, we aim to establish a baboon model of CRCI and accelerated aging. We will further define healthy aging in a baboon sample, then investigate whether chemotherapy induces cognitive decline and accelerates brain aging in baboons as it does in humans and test an intervention which has been effective in mice. We will collect brain imaging, cognitive, and aging molecular biomarker data from baboons prior to treatment with cisplatin only or cisplatin followed by an HDAC6 inhibitor. We will then collect further brain, cognitive, and aging data post-treatment to examine changes related to the chemotherapy regimen and whether the HDAC6 inhibitor reverses cognitive declines and neurodegeneration. These data will be used to propose further studies as well as techniques to potentially mitigate these consequences of chemotherapy in humans.