The role of cellular senescence in chemotherapy-related cognitive impairment

项目摘要 化疗相关的认知功能障碍（CRCI）的病因学研究不足，尽管越来越多的临床 认识到其对患者发病率的影响。改善CRCI的疾病修饰疗法迫切需要 needed.然而，这些疗法的发展受到对潜在的疾病的不完全理解的限制。 CRCI机制。长期目标是确定有助于CRCI的新细胞机制。的 本申请的总体目标是确定细胞衰老在CRCI中的作用，并定义小胶质细胞 化疗暴露后衰老的贡献。核心假设是细胞衰老 介导CRCI中的认知缺陷，并且小胶质细胞促进脑中化疗诱导的衰老。 拟议研究的基本原理是基于初步数据，显示 各种细胞群中的衰老标志物和脑内神经炎症增加的证据， 与对照组相比，有化疗史的人类尸检患者。中心假设将被检验 通过在我开发的CRCI小鼠模型中执行两个具体目标：（1）确定 衰老CRCI和（2）确定小胶质细胞在化疗诱导的发展中的作用 大脑的衰老对于第一个目的，将在转基因p16- 3 MR小鼠中诱导CRCI，以确定消融是否 的衰老细胞挽救化疗治疗的小鼠的认知表型。对于第二个目标， 在CRCI小鼠模型中，将用PLX 5622（集落刺激抑制剂）进行细胞耗竭 选择性靶向小胶质细胞的因子1受体（CSF 1 R）），以确定是否减少小胶质细胞的数量 挽救认知并减少化疗后的衰老。在这两个目标中， 中枢神经系统（CNS）的多种细胞谱系将使用多种分子和 免疫荧光和衰老相关β-半乳糖苷酶染色技术。该方法是 创新，因为强大的转基因p16- 3 MR小鼠系将用于确定衰老的作用， CRCI和小胶质细胞在介导CNS人群化疗诱导衰老中的作用， 迄今尚未评估。此外，本研究中使用的化学治疗剂是高度可接受的。 临床上与许多恶性肿瘤相关。这项研究意义重大，因为如果化疗- 大脑中的诱导衰老对认知产生不利影响，那么衰老清除疗法可能是一种有前途的新方法。 降低CRCI发病率的战略。最后，从这个建议中收集的数据将构成我未来的基础 K 08应用程序和我的研究重点作为一个独立的临床科学家。

PROJECT SUMMARY The etiology of chemotherapy-related cognitive impairment (CRCI) is understudied despite the growing clinical awareness of its contribution to patient morbidity. Disease-modifying therapies to ameliorate CRCI are urgently needed. However, development of these therapies is limited by an incomplete understanding of the underlying mechanisms of CRCI. The long-term goal is to identify novel cellular mechanisms that contribute to CRCI. The overall objective of this application is to identify the role of cellular senescence in CRCI and define the microglial contribution to senescence after chemotherapy exposure. The central hypothesis is that cellular senescence mediates cognitive deficits in CRCI and that microglia promote chemotherapy-induced senescence in the brain. The rationale for the proposed research is based on preliminary data showing increased expression of senescence markers in various cell populations and evidence of increased neuroinflammation in the brains of human autopsy patients with history of chemotherapy compared to controls. The central hypothesis will be tested by performing two specific aims in a mouse model of CRCI that I have developed: (1) identify the contribution of senescence to CRCI and (2) determine the role of microglia in the development of chemotherapy-induced senescence in the brain. For the first aim, CRCI will induced in transgenic p16-3MR mice to determine if ablation of senescent cells rescues the cognitive phenotype of chemotherapy-treated mice. For the second aim, microglia in a CRCI mouse model will be pharmacologically depleted with PLX5622 (an inhibitor of colony-stimulating factor 1 receptor (CSF1R) that selectively targets microglia) to determine if reducing the number of microglia rescues cognition and reduces measures of senescence after chemotherapy. In both aims, senescence in multiple cell lineages of the central nervous system (CNS) will be assessed using a variety of molecular and immunofluorescent and senescence-associated beta-galactosidase staining techniques. The approach is innovative because the powerful transgenic p16-3MR mice line will be used to identify the role of senescence in CRCI and the role of microglia in mediating chemotherapy-induced senescence in CNS populations, both of which have not been assessed to date. Furthermore, the chemotherapeutic agents used in this study are highly clinically relevant to a number of malignancies. The proposed research is significant because if chemotherapy- induced senescence in the brain adversely affects cognition, then senolytic therapies may be a promising new strategy to reduce the morbidity of CRCI. Finally, data collected from this proposal will form the basis of my future K08 application and my research focus as an independent clinician scientist.