Baboon model of chemotherapy-related cognitive impairment and accelerated aging

项目摘要 化疗是一种非常有效的治疗癌症的方法;然而，沿着化疗的好处 有许多不良后果，包括化疗相关的认知障碍（CRCI）， 加速老化尽管对生活质量有影响，但这些领域的研究相对不足， 目前没有FDA批准的治疗方法。一个复杂的动物模型来解决这个问题， 非常有价值，无论是对我们的长期后果的理解和发展， 潜在的治疗。目前，CRCI和化疗相关的加速老化是在啮齿动物中研究的，但 非人灵长类动物模型将大大提高解决这一问题的研究的有效性， 现象在这项研究中，我们的目标是建立一个狒狒模型的CRCI和加速老化。我们 将进一步定义狒狒样本的健康衰老，然后研究化疗是否会诱导认知能力， 降低并加速狒狒的大脑老化，就像在人类身上一样，并测试一种干预措施， 对小鼠有效。我们将从狒狒身上收集大脑成像、认知和衰老的分子生物标记数据 在仅用顺铂或顺铂随后用HDAC 6抑制剂治疗之前。我们将进一步收集 治疗后的大脑、认知和衰老数据，以检查与化疗方案相关的变化， HDAC 6抑制剂是否逆转认知能力下降和神经退行性变。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.