Cell Cycle and Metabolism in Chronically Injured Renal Tubules

慢性损伤肾小管的细胞周期和代谢

基本信息

  • 批准号:
    10661066
  • 负责人:
  • 金额:
    $ 45.34万
  • 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:
    2016-06-13 至 2026-06-30
  • 项目状态:
    未结题

项目摘要

Chronic kidney disease (CKD) affects almost 15% of Americans, and renal injury often targets the renal tubule epithelia. How these tubules respond can determine whether the kidney undergoes repair or tubulointerstitial fibrosis (TIF), the common hallmark of progressive CKD. This proposal focuses on understanding how chronic renal injury induces changes in the renal tubular cell cycle and metabolism and how these changes affect tubular survival and the development of TIF. It is well known that cell cycle, metabolism, and mitochondrial function are all closely coordinated processes, but it is not clear how epithelial G1 to S cell cycle progression affects metabolism in the CKD kidney. Preliminary data suggests that reducing cell cycle progression from G1 to S phase in renal tubules protects against fibrosis in rodent CKD models and decreases tubular apoptosis. In addition, reducing G1 to S progression increased glucose oxidation, the metabolism of glucose to pyruvate which is then oxidized in the mitochondria through the citric acid cycle and electron transport chain. This proposal will test the hypothesis that reducing epithelial G1 to S phase progression in CKD protects against epithelial injury and fibrosis through altered metabolism. To test this, Aim 1 will use either a pharmacologic (palbociclib) or a genetic (conditionally delete cyclin D1 in renal tubules) approach to reduce G1 to S cell cycle progression in mice. We hypothesize that decreasing G1 progression to S phase in epithelial cells is protective in CKD models by reducing tubular injury and fibrosis. Our preliminary data show that reducing cell cycle progression in both injured kidney tissue and in isolated tubule cells also suppresses signaling pathways and inflammatory cytokines associated with kidney injury. This aim investigates how reducing cell cycle progression may alter these signaling pathways to reduce tubule injury and myofibroblast activation by autocrine and paracrine signaling, respectively. The second aim investigates the metabolic changes that occur in injured tubules with reduced G1 to S phase progression using the Seahorse bioflux analyzer, 14C-pyruvate oxidation studies ex vivo, and stable isotopic metabolomics. We hypothesize that reducing epithelial cell cycle progression increases glucose oxidation leading to better epithelial survival and less fibrosis, in part, through the AMP-activated protein kinase pathway. We will also investigate how glucose oxidation in renal tubules, independent of metabolism, affects the response to chronic injury. The impact of cell cycle progression on mitochondrial function and structure will also be defined using Oroboros and super- resolution microscopy. These studies should provide novel information about how changes in epithelial cell cycle and metabolism affect the response to chronic renal injury with the potential identification of novel therapeutic targets to treat CKD.
慢性肾脏疾病(CKD)影响了近15%的美国人,肾脏损伤通常针对的是肾小管 上皮细胞。这些小管的反应可以决定肾脏是经历修复还是肾小管间质 纤维化(TIF),进展性CKD的共同标志。这项建议的重点是了解慢性 肾损伤引起肾小管细胞周期和代谢的改变及其影响 肾小管存活和TIF的发展。众所周知,细胞周期、新陈代谢和线粒体 功能都是密切协调的过程,但尚不清楚上皮性G1是如何向S细胞周期推进的 影响CKD肾脏的新陈代谢。初步数据表明,减少细胞周期从G1期进展 肾小管S时相对慢性肾功能不全大鼠肾小管纤维化的保护作用及减少肾小管细胞凋亡的作用。在……里面 另外,降低G1至S级数增加葡萄糖氧化,将葡萄糖代谢为丙酮酸 然后通过柠檬酸循环和电子传输链在线粒体中氧化。这 该提案将检验将慢性肾脏病上皮细胞G1期进展减少到S期进展对保护作用的假设 通过改变新陈代谢来对抗上皮损伤和纤维化。为了测试这一点,Aim 1将使用 药物(Palbociclib)或遗传方法(有条件地删除肾小管中的细胞周期蛋白D1)减少G1 对S小鼠细胞周期进程的影响。我们假设上皮细胞G1期进展到S期 在CKD模型中,细胞通过减少肾小管损伤和纤维化而起到保护作用。我们的初步数据显示, 减少受损肾组织和分离的肾小管细胞的细胞周期进程也会抑制 与肾损伤相关的信号通路和炎性细胞因子。这一目标调查了 减少细胞周期进程可能改变这些信号通路,以减少肾小管损伤和肌成纤维细胞 分别通过自分泌和旁分泌信号激活。第二个目的是研究新陈代谢 使用海马氏生物通量在损伤的小管中发生的变化,其中G1期到S期进展减少 ~(14)C-丙酮酸体外氧化研究和稳定同位素代谢组学。我们假设 减缓上皮细胞周期进程增加葡萄糖氧化导致更好的上皮存活和 较少的纤维化,部分是通过AMP激活的蛋白激酶途径。我们还将研究葡萄糖是如何 肾小管的氧化作用独立于新陈代谢,影响对慢性损伤的反应。细胞的影响 线粒体功能和结构的循环进程也将使用Oroboros和Super- 分辨率显微镜。这些研究应该为上皮细胞如何变化提供新的信息 周期和代谢对慢性肾损伤反应的影响及其潜在的新鉴定 治疗CKD的靶点。

项目成果

期刊论文数量(10)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Leslie S Gewin其他文献

Leslie S Gewin的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Leslie S Gewin', 18)}}的其他基金

Metabolism Core
新陈代谢核心
  • 批准号:
    10747722
  • 财政年份:
    2023
  • 资助金额:
    $ 45.34万
  • 项目类别:
Epithelial Beta-catenin Signaling Improves Chronic Renal Injury
上皮β-连环蛋白信号传导改善慢性肾损伤
  • 批准号:
    10266013
  • 财政年份:
    2018
  • 资助金额:
    $ 45.34万
  • 项目类别:
Epithelial Beta-catenin Signaling Improves Chronic Renal Injury
上皮β-连环蛋白信号传导改善慢性肾损伤
  • 批准号:
    10612208
  • 财政年份:
    2018
  • 资助金额:
    $ 45.34万
  • 项目类别:
Cell Cycle and Metabolism in Chronically Injured Renal Tubules
慢性损伤肾小管的细胞周期和代谢
  • 批准号:
    10366536
  • 财政年份:
    2016
  • 资助金额:
    $ 45.34万
  • 项目类别:
Cell Cycle and Metabolism in Chronically Injured Renal Tubules
慢性损伤肾小管的细胞周期和代谢
  • 批准号:
    10493373
  • 财政年份:
    2016
  • 资助金额:
    $ 45.34万
  • 项目类别:
TGF-beta Pathways that Protect Epithelia in Chronic Renal Injury
慢性肾损伤中保护上皮细胞的 TGF-β 通路
  • 批准号:
    9294119
  • 财政年份:
    2016
  • 资助金额:
    $ 45.34万
  • 项目类别:
TGF-beta Pathways that Protect Epithelia in Chronic Renal Injury
慢性肾损伤中保护上皮细胞的 TGF-β 通路
  • 批准号:
    9337599
  • 财政年份:
    2016
  • 资助金额:
    $ 45.34万
  • 项目类别:

相似海外基金

Pharmacological targeting of AMP-activated protein kinase for immune cell regulation in Type 1 Diabetes
AMP 激活蛋白激酶对 1 型糖尿病免疫细胞调节的药理学靶向
  • 批准号:
    2867610
  • 财政年份:
    2023
  • 资助金额:
    $ 45.34万
  • 项目类别:
    Studentship
Establishing AMP-activated protein kinase as a regulator of adipose stem cell plasticity and function in health and disease
建立 AMP 激活蛋白激酶作为脂肪干细胞可塑性和健康和疾病功能的调节剂
  • 批准号:
    BB/W009633/1
  • 财政年份:
    2022
  • 资助金额:
    $ 45.34万
  • 项目类别:
    Fellowship
Determining the role of AMP-activated protein kinase in the integration of skeletal muscle metabolism and circadian biology
确定 AMP 激活蛋白激酶在骨骼肌代谢和昼夜节律生物学整合中的作用
  • 批准号:
    532989-2019
  • 财政年份:
    2021
  • 资助金额:
    $ 45.34万
  • 项目类别:
    Postdoctoral Fellowships
Metabolic control of integrin membrane traffic by AMP-activated protein kinase controls cell migration.
AMP 激活的蛋白激酶对整合素膜运输的代谢控制控制着细胞迁移。
  • 批准号:
    459043
  • 财政年份:
    2021
  • 资助金额:
    $ 45.34万
  • 项目类别:
    Studentship Programs
Determining the role of AMP-activated protein kinase in the integration of skeletal muscle metabolism and circadian biology
确定 AMP 激活蛋白激酶在骨骼肌代谢和昼夜节律生物学整合中的作用
  • 批准号:
    532989-2019
  • 财政年份:
    2020
  • 资助金额:
    $ 45.34万
  • 项目类别:
    Postdoctoral Fellowships
The Role of AMP-activated Protein Kinase in GVHD-causing T Cells
AMP 激活的蛋白激酶在引起 GVHD 的 T 细胞中的作用
  • 批准号:
    10561642
  • 财政年份:
    2019
  • 资助金额:
    $ 45.34万
  • 项目类别:
Determining the role of AMP-activated protein kinase in the integration of skeletal muscle metabolism and circadian biology
确定 AMP 激活蛋白激酶在骨骼肌代谢和昼夜节律生物学整合中的作用
  • 批准号:
    532989-2019
  • 财政年份:
    2019
  • 资助金额:
    $ 45.34万
  • 项目类别:
    Postdoctoral Fellowships
Treating Diabetic Inflammation using AMP-Activated Protein Kinase Activators
使用 AMP 激活的蛋白激酶激活剂治疗糖尿病炎症
  • 批准号:
    2243045
  • 财政年份:
    2019
  • 资助金额:
    $ 45.34万
  • 项目类别:
    Studentship
The Role of AMP-activated Protein Kinase in GVHD-causing T Cells
AMP 激活的蛋白激酶在引起 GVHD 的 T 细胞中的作用
  • 批准号:
    10359032
  • 财政年份:
    2019
  • 资助金额:
    $ 45.34万
  • 项目类别:
Investigating the therapeutic potential of AMP-activated protein kinase in myotonic dystrophy type 1
研究 AMP 激活蛋白激酶在 1 型强直性肌营养不良中的治疗潜力
  • 批准号:
    428988
  • 财政年份:
    2019
  • 资助金额:
    $ 45.34万
  • 项目类别:
    Studentship Programs
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了