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The role of cellular senescence in chemotherapy-related cognitive impairment

细胞衰老在化疗相关认知障碍中的作用

基本信息

批准号：
10327602
负责人：
Matthew Torre
金额：
$ 5.87万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-01 至 2022-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10327602
关键词：
Ablation Address Adverse effects Affect Aging Alzheimer&apos s disease model Autopsy Awareness Brain Cell Aging Cell Cycle Arrest Cell Lineage Cells Chronic Clinical Cognition Cognitive Cognitive deficits DNA Damage Data Development Disease Employment Etiology Functional disorder Future Genetic Goals Human Iatrogenesis Inflammation Investigation Macrophage Colony-Stimulating Factor Receptor Malignant Neoplasms Measures Mediating Mediator of activation protein Memory Microglia Mission Molecular Morbidity - disease rate Mus Nerve Degeneration Neuraxis Neurocognitive Neuroglia Neurons Outcome Oxidative Stress Pathway interactions Patients Peptide Hydrolases Pharmacology Phenotype Population Quality of life Reactive Oxygen Species Recording of previous events Research Role Scientist Source Stains Techniques Testing Tissues Transgenic Organisms Water base beta-Galactosidase brain cell brain tissue career chemobrain chemokine chemotherapeutic agent chemotherapy clinically relevant cognitive function cognitive performance cytokine cytotoxic dysmyelination human data improved inhibitor innovation mouse model neuroinflammation neuropathology novel reduce symptoms senescence therapeutic target therapy development

项目摘要

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.

项目总结尽管临床上对化疗相关认知功能障碍(CRCI)的研究越来越多，但其病因仍未得到充分研究意识到它对患者发病率的贡献。改善慢性心肌梗死的疾病修饰疗法迫在眉睫需要的。然而，这些疗法的发展受到对潜在疾病的不完全理解的限制。 CRCI的发病机制。长期目标是确定对CRCI有贡献的新的细胞机制。这个这项应用的总体目标是确定细胞衰老在CRCI中的作用，并定义小胶质细胞对化疗暴露后衰老的贡献。中心假说是细胞衰老调节CRCI的认知缺陷，小胶质细胞促进化疗诱导的大脑衰老。这项拟议研究的理由是基于初步数据显示，不同细胞群中的衰老标记物和脑内神经炎症增加的证据有化疗史的尸检患者与对照组进行比较。核心假说将得到检验通过在我开发的CRCI小鼠模型中实现两个特定目的：(1)确定 CRCI的衰老和(2)确定小胶质细胞在化疗诱导的肿瘤发展中的作用大脑中的衰老。对于第一个目的，将在转基因p16-3mr小鼠中诱导CRCI，以确定是否消融衰老细胞的存在挽救了化疗小鼠的认知表型。对于第二个目的，小胶质细胞在CRCI小鼠模型中，PLX5622(一种集落刺激抑制剂)将在药物上耗尽选择性靶向小胶质细胞的因子1受体(CSF1R)，以确定是否减少小胶质细胞的数量挽救认知，减少化疗后衰老的措施。在这两个目标中，衰老中枢神经系统(CNS)的多种细胞谱系将使用各种分子和免疫荧光和衰老相关的β-半乳糖苷酶染色技术。方法是创新是因为强大的转基因p16-3MR小鼠品系将被用来识别衰老在 CRCI和小胶质细胞在中枢神经系统人群化疗诱导衰老中的作用到目前为止还没有评估过。此外，这项研究中使用的化疗药物高度在临床上与许多恶性肿瘤有关。这项拟议的研究意义重大，因为如果化疗- 大脑的诱导衰老会对认知产生不利影响，那么衰老治疗可能是一种很有前途的新疗法降低CRCI发病率的策略。最后，从这项提案中收集的数据将构成我未来的基础 K08的应用和我作为一名独立临床科学家的研究重点。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Methyl-Branched Liposomes as a Depot for Sustained Drug Delivery.

甲基支化脂质体作为持续药物递送的储存库。

DOI：
10.1021/acs.nanolett.3c02137
发表时间：
2023
期刊：
Nano letters
影响因子：
10.8
作者：
Li,Yang;Shao,Rachelle;Ostertag-Hill,ClaireA;Torre,Matthew;Yan,Ran;Kohane,DanielS
通讯作者：
Kohane,DanielS

A Drosophila model of chemotherapy-related cognitive impairment.

化疗相关认知障碍的果蝇模型。

DOI：
10.1101/2023.06.01.543297
发表时间：
2023
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Torre,Matthew;Bukhari,Hassan;Nithianandam,Vanitha;Zanella,CamilaA;Mata,DouglasA;Feany,MelB
通讯作者：
Feany,MelB

Elevated Oxidative Stress and DNA Damage in Cortical Neurons of Chemotherapy Patients.

化疗患者皮质神经元氧化应激升高和 DNA 损伤。