Understanding Epithelial Plasticity in Renal Repair after Acute Kidney Injury

了解急性肾损伤后肾脏修复中的上皮可塑性

基本信息

  • 批准号:
    9767783
  • 负责人:
  • 金额:
    $ 44.6万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-08-21 至 2023-06-30
  • 项目状态:
    已结题

项目摘要

Understanding Epithelial Plasticity in Renal Repair after Acute Kidney Injury Following acute kidney injury (AKI), surviving tubular epithelial cells (TECs) proliferate and regenerate the injured epithelium leading to kidney function recovery. However, until recently, the intrinsic molecular driver of epithelial regeneration remained elusive. To this end, we recently identified SOX9 as the molecular driver that regenerates the injured epithelium. Coupling genetic lineage strategy to tissue-specific, conditional knock-out methodology, we identified SOX9 as a direct, intrinsic molecular link between repair and formation of the nephron tubular epithelia. Upon successful regeneration of the epithelia after injury, SOX9 attained baseline level. However, during progression of ischemic AKI to chronic kidney disease (CKD), distinct, sporadic persistently injured TECs mounted a strong sustained SOX9 (sSOX9+) with cell proliferation signature thereby demarcating “unresolved injury/repair cell-type”. These findings raise crucial unanswered questions, including: (1) does human kidneys activate SOX9 after AKI, (2) how an injured epithelium rapidly mounts a SOX9 pro- replicative response, (3) how SOX9 drive epithelial regeneration and whether upon activation it dedifferentiates the injured TECs to its embryonic progenitor-like state to drive repair, and (4) whether sSOX9+ contributes to the progression of AKI to CKD. To this end, here we further identify (a) SOX9 activation after human AKI, (b) a nuclear phosphoEGFR:SOX9 pro-replicative axis in both primary mice and human proximal TECs, and (c) intimate, robust association of sSOX9+ cells with αSMA+ myofibroblasts. The proposed research will test (Aim 1) the hypothesis that injury induced EGFR signaling via nuclear phosphorylated EGFR activates Sox9 and exerts Sox9-dependent pro-reparative effects, with Sox9 per se being sufficient to drive proliferation; (Aim 2) will reveal molecular underpinnings of Sox9-orchestrated reparative action whilst determining whether injury- activated Sox9 dedifferentiates the injured PTECs to a progenitor-like state; (Aim 3) test the hypothesis that sustained Sox9+ subset demarcating “unresolved injury/repair” cell-type contribute to progression of AKI to CKD. The proposed research is innovative because using state-of-the-art approaches we will critically investigate the above heretofore-unexamined molecular and cellular pathways in renal repair. The proposed research is significant and impactful because (A) our findings akin to our mice studies highlight SOX9 activation within the PTECs after human ischemic AKI and SOX9-based pro-replicative responses in human primary proximal tubular epithelial cells; and (B) injury-induced epithelial plasticity is a poorly understood process, and deep, critical insights gained by the proposed research work will advance not only kidney field but will have direct application to the mechanistic understanding of tissue remodeling in other epithelial-based organ systems. Better understanding of such processes is crucial in the development of therapies aimed to harness and augment endogenous reparative processes while simultaneously blocking pro-fibrotic responses.
了解急性肾损伤后肾修复中的上皮可塑性

项目成果

期刊论文数量(0)
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 }}

Sanjeev Kumar其他文献

Sanjeev Kumar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('Sanjeev Kumar', 18)}}的其他基金

Understanding Epithelial Plasticity in Renal Repair after Acute Kidney Injury
了解急性肾损伤后肾脏修复中的上皮可塑性
  • 批准号:
    10438573
  • 财政年份:
    2018
  • 资助金额:
    $ 44.6万
  • 项目类别:
Understanding Epithelial Plasticity in Renal Repair after Acute Kidney Injury
了解急性肾损伤后肾脏修复中的上皮可塑性
  • 批准号:
    10188520
  • 财政年份:
    2018
  • 资助金额:
    $ 44.6万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了