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HIV infection-induced mitochondrial dysfunction and premature T cell aging

HIV infection-induced mitochondrial dysfunction and premature T cell aging
HIV感染引起的线粒体功能障碍和T细胞过早衰老
批准号:
10203459
负责人:
Zhi Q. Yao
金额:
$42.76万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
已结题
起止时间:
2021-09-05 至 2024-08-31

项目摘要

项目成果

Zhi Q. Yao的其他基金

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中文摘要
翻译
HIV感染诱导线粒体功能障碍和T细胞过早老化
英文摘要
HIV infection-induced mitochondrial dysfunction and premature T cell aging HIV infection appears to drive premature T cell aging, evidenced by mitochondrial dysfunction. How CD4 T cells develop mitochondrial dysfunction during HIV infections is unclear. The objective of this proposal is to elucidate the mechanisms of mitochondrial dysfunction during chronic HIV infection, so as to develop effective means to rescue CD4 T cell depletion or functional impairment, the sine que non of HIV-infection. To elucidate the mechanisms underlying mitochondrial dysfunction in CD4 T cell aging, we analyzed the mitochondrial function of CD4 T cells derived from ART-controlled HIV patients. Our preliminary data show that HIV CD4 T cells have decreased mitochondrial DNA (mtDNA) content, mitochondrial respiration, and ATP production. To identify candidate proteins involved in dysregulating mtDNA copy numbers, we performed Liquid Chromatography Mass Spectrometry (LC-MS) on purified mitochondria from CD4 T cells of HIV patients and health subjects (HS). We found largest reduction of mitochondrial proteins (SOD1 and PRDX1) in destroying reactive oxygen species (ROS), and in repair of ROS- mediated DNA damage repair (APEX1), and elevation of proteins in mtDNA degrading (EXOG and ENDOG) and mtDNA replication (POLG and MGME1). Based on these and other preliminary data, we hypothesize that ROS- mediated mtDNA damage (via lower SOD1 and/or PDRX1 and APEX1) may cause higher mtDNA degradation (by EXOG and ENDOG), which may not be sufficiently complemented by mtDNA replication (through higher POLG and MGME1), leading to lower mtDNA copy number and impaired mitochondrial functions that we have seen in HIV- derived CD4 T cells. We propose two aims to define the mechanisms leading to mtDNA decrease and compromised function. In Aim 1, We will determine if ectopic expression of SOD1 and/or PRDX1 can reduce ROS level and oxidative mtDNA damage in CD4 T cells of HIV patients. In addition, ectopic expression of APEX1 will be performed to determine the involvement of APEX1 in repairing damaged mtDNA via the base excision repair (BER) pathway. siRNA knockdown of SOD1 and/or PRDX1, and APEX1 will also be performed in healthy CD4 T cells to confirm their roles in mtDNA damage and copy number maintenance, mitochondrial respiration, and ATP production. In Aim 2, we will use transient siRNA knockdown or Crisper/Cas9 knockout to reduce the EXOG and/or ENDOG nucleases in CD4 T cells from HIV patients, and to assess the levels of oxidative mtDNA damage and rescue of mtDNA copy number. We will perform single molecule analysis of replicated DNA (SMARD) on mtDNA in cultured CD4 T cells from HIV patients to comprehensively assess the status of mtDNA replication in response to T cell receptor (TCR) stimulation. Overall, this application is novel and strong in both concept and approach to answer clinically relevant questions: how chronic viral infection induces mitochondrial dysfunction, leading to premature T cells aging, and whether interfering those over-activated enzymes responsible for mtDNA copy number reduction and mitochondrial dysfunction can remodel T cell aging and function during HIV infection. Understanding such mechanisms is critical for developing approaches to improve immune responses in the setting of many infectious or inflammatory diseases.
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Dual specific gene editing drugs delivered by nanoparticles targeting HBV/HIV coinfection
  • 批准号:
    10403587
  • 项目类别:
  • 资助金额:
    $18.56万
  • 财政年份:
    2021
  • 负责人:
    Zhi Q. Yao
  • 依托单位:
Mitochondrial Dysfunction in Aging CD4 T cells in HIV-immune Non-responders.
  • 批准号:
    10845843
  • 项目类别:
  • 资助金额:
    $37.5万
  • 财政年份:
    2021
  • 负责人:
    Zhi Q. Yao
  • 依托单位:
Dual specific gene editing drugs delivered by nanoparticles targeting HBV/HIV coinfection
  • 批准号:
    10161447
  • 项目类别:
  • 资助金额:
    $23.42万
  • 财政年份:
    2021
  • 负责人:
    Zhi Q. Yao
  • 依托单位:
Multiuser Advanced Confocal Microscope