(PQ9)A redox-mediated mechanism of chemotherapy-induced cognitive impairment

(PQ9)化疗引起的认知障碍的氧化还原介导机制

基本信息

  • 批准号:
    9363914
  • 负责人:
  • 金额:
    $ 45.51万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-09-15 至 2022-07-31
  • 项目状态:
    已结题

项目摘要

Project Summary This application addresses the Provocative Question 9: "What are the molecular and/or cellular mechanisms that underlie the development of cancer therapy-induced severe adverse sequelae?" focusing on Chemotherapy-induced cognitive impairments (CICI). CICI is now a recognized toxicity syndrome that includes loss of executive function (confusion; memory issues), inability to multitask, and impaired intellectual reasoning. While CICI caused by central nervous system (CNS)-directed therapies (such as radiation and intrathecal chemotherapy) is readily understood, the mechanisms underlying a critical and shared toxicity of chemotherapy that occurs after systemic cancer treatment with drugs that did not direct at the brain, are unclear. The number of patients at risk for CICI from systemic therapy far exceeds the number of patients exposed to CNS therapy, but little is known about the mechanisms mediating the effect of systemic therapy on CICI, and there is no clear vision of how to prevent this condition. We have previously shown that generation of reactive oxygen species (ROS) by cytotoxic chemotherapeutic drugs is an essential mediator of brain injury even though the drug itself did not get into the brain. It is also imperative to note that anticancer medications, designed specifically to target cancer cells with specialized features, such as the family of Bcl2 inhibitors, also generate ROS. However, the effect of targeted therapy on CICI has never been addressed, and, consequently, their mechanisms of action are entirely unknown. The goal of this proposal is to test the overall hypothesis that therapy-induced ROS production in the target tissues leads to increased circulating TNFα through extracellular vesicles (EVs)-mediated reactions, and this pro-inflammatory cytokine crosses the blood brain barrier to elicit mitochondrial dysfunction and consequent neuronal injury leading to CICI. The following specific aims are designed to test the ROS hypothesis, gain an understanding of the EVs-mediated mechanisms, and test the proof-of-concept in an experimental cancer therapy setting using two prototype chemotherapy agents (Doxorubicin and Venetoclax) that represent standard cytotoxic and experimental targeted drugs in a lymphoma model. Aim 1 will investigate the fundamental role of TNFα in therapy-induced neuronal injury to gain insights into mechanisms of CICI in the brain and demonstrate efficacy of chemotherapy in the presence of redox-active antioxidants. Aim 2 will determine the mechanistic links between circulating extracellular vesicles and therapy-induced CICI. Aim 3 will define the cell(s) of origin of TNFα produced during chemotherapy that leads to cognitive impairment. These aims will be accomplished in vitro and in vivo using state-of-the-art technologies, including magnetic resonance spectroscopy, redox proteomics, unique animal models, and novel mitochondria targeting anti-oxidant, MnP, to ameliorate CICI without reducing the efficacy of the anti-cancer drugs. The results from this project will lay important groundwork for future clinical trials to improve the quality of lives of cancer patients exposed to cytotoxic or targeted therapies.
项目总结

项目成果

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专利数量(0)

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SUBBARAO BONDADA其他文献

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{{ truncateString('SUBBARAO BONDADA', 18)}}的其他基金

(PQ9)A redox-mediated mechanism of chemotherapy-induced cognitive impairment
(PQ9)化疗引起的认知障碍的氧化还原介导机制
  • 批准号:
    9982850
  • 财政年份:
    2017
  • 资助金额:
    $ 45.51万
  • 项目类别:
(PQ9)A redox-mediated mechanism of chemotherapy-induced cognitive impairment
(PQ9)化疗引起的认知障碍的氧化还原介导机制
  • 批准号:
    10216188
  • 财政年份:
    2017
  • 资助金额:
    $ 45.51万
  • 项目类别:
Role of Tcl1 and Par-4 in regulation of chronic lymphocytic leukemia
Tcl1和Par-4在慢性淋巴细胞白血病的调节中的作用
  • 批准号:
    8792347
  • 财政年份:
    2013
  • 资助金额:
    $ 45.51万
  • 项目类别:
Role of Tcl1 and Par-4 in regulation of chronic lymphocytic leukemia
Tcl1和Par-4在慢性淋巴细胞白血病的调节中的作用
  • 批准号:
    9205218
  • 财政年份:
    2013
  • 资助金额:
    $ 45.51万
  • 项目类别:
Role of Tcl1 and Par-4 in regulation of chronic lymphocytic leukemia
Tcl1和Par-4在慢性淋巴细胞白血病的调节中的作用
  • 批准号:
    8440656
  • 财政年份:
    2013
  • 资助金额:
    $ 45.51万
  • 项目类别:
Role of Tcl1 and Par-4 in regulation of chronic lymphocytic leukemia
Tcl1和Par-4在慢性淋巴细胞白血病的调节中的作用
  • 批准号:
    8616359
  • 财政年份:
    2013
  • 资助金额:
    $ 45.51万
  • 项目类别:
Role of Tcl1 and Par-4 in regulation of chronic lymphocytic leukemia
Tcl1和Par-4在慢性淋巴细胞白血病的调节中的作用
  • 批准号:
    8997402
  • 财政年份:
    2013
  • 资助金额:
    $ 45.51万
  • 项目类别:
Importance of CD5 for the function of regulatory T cells
CD5 对于调节性 T 细胞功能的重要性
  • 批准号:
    7640703
  • 财政年份:
    2008
  • 资助金额:
    $ 45.51万
  • 项目类别:
Importance of CD5 for the function of regulatory T cells
CD5 对于调节性 T 细胞功能的重要性
  • 批准号:
    7471782
  • 财政年份:
    2008
  • 资助金额:
    $ 45.51万
  • 项目类别:
Growth Regulation and Therapy of Leukemias and Lymphomas
白血病和淋巴瘤的生长调节和治疗
  • 批准号:
    7122013
  • 财政年份:
    2003
  • 资助金额:
    $ 45.51万
  • 项目类别:

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