AMP Kinase Activation in Calcineurin Inhibitor Nephrotoxicity

钙调神经磷酸酶抑制剂肾毒性中的 AMP 激酶激活

基本信息

  • 批准号:
    9235872
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-10-01 至 2020-09-30
  • 项目状态:
    已结题

项目摘要

Solid organ transplantation necessitates the use of lifelong immunosuppression. In particular, the calcineurin inhibitors (CNIs) are utilized in nearly all transplant recipients as they are potent immunosuppressants. In kidney transplantation, the use of CNIs has led to the very low rejection rates of ~7-10% per year. However, long term graft survival has not improved substantially with their utilization, with a mean half-life of 10 years for kidney transplants. A key contributor to late graft injury is CNI-nephrotoxicity which is manifested by declining kidney function and the histological features of interstitial fibrosis, tubular atrophy, and arteriolar hyalinosis. The mechanism by which CNI induce kidney injury and failure is multifactorial, and to date, there are no specific therapeutic strategies to mitigate this injury. The goal of this submission is to identify a novel and clinically applicable strategy to ameliorate CNI-associated kidney injury. Recently, AMP-Activated Protein Kinase (AMPK), a key regulator of cell metabolism, autophagy, and mitochondrial biogenesis, has been linked to modulating kidney injury. Further, loss of AMPK activation is associated with organ inflammation and fibrosis. We hypothesize that AMPK activation could ameliorate some of the adverse metabolic consequences in renal tubular epithelium and as a corollary, AMPK activation could be a clinically relevant intervention to mitigate long term CNI nephrotoxicity. Our study will focus on cyclosporine A (CsA), a classic CNI therapeutic agent. We will utilize a complementary series of studies, both in vitro and in vivo, using a mouse model of CsA injury that we have used successfully in our laboratory. In vitro, we will focus on renal tubular epithelium, the primary target of in vivo injury. We will study both the impact of AMPK activation as well as knock down using pharmacologic agents and silencing RNAs. Outcomes will include assessments of bioenergetics, mitochondrial function, pro-inflammatory markers and the DAMP HMGB1, and paracrine impact on macrophages and their differentiation. In vivo, we will test the impact of AMPK activation on ameliorating CsA renal injury by assessing kidney function (serum creatinine), mRNA expression of inflammatory mediators within the kidney, and biochemical, cellular and histologic assessments of injury and fibrosis. We will assess both pre-emptive inhibition as well as determine the impact of AMPK activation after established CsA nephrotoxicity. To complement these pharmacologic studies, we will also employ the novel use of AMPK 1 and 2 deficient mice. Cross-transplant studies will allow us to dissect the role of systemic versus renal expression of AMPK in injury. We believe that this comprehensive approach will provide key mechanistic insights into ameliorating or mitigating CNI nephrotoxicity. The use of a clinically relevant activator, metformin, will provide an opportunity for rapid translation into our human recipients of kidneys and other solid organ transplants.
实体器官移植需要终身免疫抑制。尤其是钙调磷酸酶

项目成果

期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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ROSLYN B MANNON其他文献

ROSLYN B MANNON的其他文献

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{{ truncateString('ROSLYN B MANNON', 18)}}的其他基金

AMP Kinase Activation in Calcineurin Inhibitor Nephrotoxicity
钙调神经磷酸酶抑制剂肾毒性中的 AMP 激酶激活
  • 批准号:
    10187188
  • 财政年份:
    2016
  • 资助金额:
    --
  • 项目类别:
AMP Kinase Activation in Calcineurin Inhibitor Nephrotoxicity
钙调神经磷酸酶抑制剂肾毒性中的 AMP 激酶激活
  • 批准号:
    10204706
  • 财政年份:
    2016
  • 资助金额:
    --
  • 项目类别:
REGULATION OF THYMOCYTE APOPTOSIS BY THROMBOXANE A2
血栓烷A2对胸腺细胞凋亡的调节
  • 批准号:
    6169407
  • 财政年份:
    1996
  • 资助金额:
    --
  • 项目类别:
REGULATION OF THYMOCYTE APOPTOSIS BY THROMBOXANE A2
血栓烷A2对胸腺细胞凋亡的调节
  • 批准号:
    2886027
  • 财政年份:
    1996
  • 资助金额:
    --
  • 项目类别:
REGULATION OF THYMOCYTE APOPTOSIS BY THROMBOXANE A2
血栓烷A2对胸腺细胞凋亡的调节
  • 批准号:
    2057692
  • 财政年份:
    1996
  • 资助金额:
    --
  • 项目类别:
REGULATION OF THYMOCYTE APOPTOSIS BY THROMBOXANE A2
血栓烷A2对胸腺细胞凋亡的调节
  • 批准号:
    2390118
  • 财政年份:
    1996
  • 资助金额:
    --
  • 项目类别:
REGULATION OF THYMOCYTE APOPTOSIS BY THROMBOXANE A2
血栓烷A2对胸腺细胞凋亡的调节
  • 批准号:
    2671413
  • 财政年份:
    1996
  • 资助金额:
    --
  • 项目类别:

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