Molecular mechanisms of cold storage-induced damage to the corneal endothelium

冷藏引起角膜内皮损伤的分子机制

基本信息

  • 批准号:
    10741168
  • 负责人:
  • 金额:
    $ 43.22万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-09-30 至 2025-08-31
  • 项目状态:
    未结题

项目摘要

Molecular mechanisms of cold storage-induced damage to the corneal endothelium The endothelium at the posterior surface of the cornea is a non-regenerative monolayer. It maintains corneal transparency through its barrier and fluid pump functions. Thus, a rapid decline in endothelial cell density (ECD), observed during genetic disorders or in response to intraocular surgery, disturbs corneal transparency. Moreover, since there are no drugs to halt endothelial cell loss (ECL) during these disorders, corneal transplantation is the standard of care when ECD < 600-800 cells/mm2. In 2021, > 49,000 transplants were carried out in the USA at the cost of ~ $40,000/transplant. In addition to the gift of sight, the procedure saved an estimated lifetime value of $5.8 Billion. Although corneal transplants are more successful than other solid organ transplants, delayed recovery of corneal transparency and a rapid decline in ECD after the surgery are two significant challenges yet to be fully understood. The decrease in the ECD after surgery is in addition to ECL that occurs during cold storage (CS). However, the molecular mechanisms for ECL during CS or acute ECL after surgery are unknown. Our recent studies have shown that CS adversely impacts the endothelium. Specifically, when freshly isolated porcine corneas were held in prolonged CS (> 3 days at 4 C), endothelium exhibited microtubule (MT) disassembly, destruction of its peri-junctional actomyosin ring (PAMR), lipid peroxidation, and cell death. These effects were inhibited by including antioxidants or iron chelators (deferoxamine) in the CS medium. Thus, we hypothesize that CS induces oxidative stress in the endothelium, leading to (a) a breakdown of its tight junctions via the destruction of its PAMR and (b) the formation of islands of denuded Descemet’s membrane (iDDMs) because of cell death. To regain corneal transparency, the extreme loss in barrier function must be corrected by the repopulation of iDDMs and normalization of the tight junctions. The main goal of this project is to test all our hypotheses based on two specific aims. First, in Aim 1, we will determine how CS induces mitochondrial dysfunction in the endothelium, leading to oxidative stress. We will also assess if the mode of cell death also involves ferroptosis. Subsequently, in Aim 2, we will determine how oxidative stress destroys the PAMR, thereby causing a breakdown of tight junctions. In addition, we will test the assumption that the repopulation of iDDMs is slowed by oxidative stress prevailing in the endothelium, leading to a delay in the rapid recovery of corneal transparency after CS. Overall, this project will dissect the molecular mechanisms that adversely affect the endothelium during CS. We expect our findings to enable pharmacological approaches by which we can limit ECL during CS and acutely after surgery for enhanced corneal transplantation.
低温保存对角膜内皮细胞损伤的分子机制 角膜后表面的内皮是非再生单层。保持角膜 通过其屏障和流体泵功能实现透明性。因此,内皮细胞密度(ECD)的快速下降, 在遗传性疾病期间或眼内手术时观察到,干扰角膜透明度。 此外,由于没有药物来阻止这些疾病期间的内皮细胞损失(ECL),角膜内皮细胞损伤可能会导致角膜内皮细胞的损伤。 当ECD < 600-800个细胞/mm 2时,移植是护理标准。2021年,超过49,000例移植手术 在美国进行,费用约为40,000美元/移植。除了视力的礼物,这个程序节省了一个 估计终身价值58亿美元。 虽然角膜移植比其他实体器官移植更成功,但角膜移植术后的延迟恢复, 透明度和手术后ECD的快速下降是两个尚未完全解决的重大挑战。 明白手术后ECD的降低是在冷藏(CS)期间发生的ECL之外的。 然而,CS期间ECL或手术后急性ECL的分子机制尚不清楚。 我们最近的研究表明,CS对内皮细胞有不利影响。特别是,当新鲜分离时, 将猪角膜长期置于CS中(4 ℃下> 3天),内皮细胞显示微管(MT) 解体,其连接周围肌动球蛋白环(PAMR)的破坏,脂质过氧化和细胞死亡。这些 通过在CS培养基中包括抗氧化剂或铁螯合剂(去铁胺)来抑制作用。因此我们 假设CS诱导内皮细胞的氧化应激,导致(a)其紧密连接的破坏 通过破坏其PAMR和(B)形成裸露的后弹力膜岛(iDDM) 因为细胞死亡。为了恢复角膜透明度,必须通过以下方法来纠正屏障功能的极度丧失: iDDM的再增殖和紧密连接的正常化。这个项目的主要目标是测试我们所有的 基于两个具体目标的假设。首先,在目标1中,我们将确定CS如何诱导线粒体 内皮功能障碍,导致氧化应激。我们还将评估细胞死亡的方式是否也 包括铁性下垂随后,在目标2中,我们将确定氧化应激如何破坏PAMR,从而 导致紧密连接的破坏。此外,我们还将检验iDDM的再增殖假设 由于内皮细胞中普遍存在的氧化应激而减慢,导致角膜的快速恢复延迟。 CS之后的透明性。总的来说,这个项目将剖析分子机制,不利地影响 CS期间的内皮细胞。我们希望我们的发现能够使药理学方法,我们可以限制 增强型角膜移植术后CS期间和急性ECL。

项目成果

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SANGLY P SRINIVAS其他文献

SANGLY P SRINIVAS的其他文献

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{{ truncateString('SANGLY P SRINIVAS', 18)}}的其他基金

Kinetics of Drug Penetration Across the Cornea at a Microscopic Level
微观水平上药物穿过角膜的渗透动力学
  • 批准号:
    7511172
  • 财政年份:
    2008
  • 资助金额:
    $ 43.22万
  • 项目类别:
Kinetics of Drug Penetration Across the Cornea at a Microscopic Level
微观水平上药物穿过角膜的渗透动力学
  • 批准号:
    7681034
  • 财政年份:
    2008
  • 资助金额:
    $ 43.22万
  • 项目类别:
Myocilin-induced ER Stress in Trabecular Meshwork Cells
肌纤蛋白诱导的小梁网细胞内质网应激
  • 批准号:
    6914435
  • 财政年份:
    2003
  • 资助金额:
    $ 43.22万
  • 项目类别:
Myocilin-induced ER Stress in Trabecular Meshwork Cells
肌纤蛋白诱导的小梁网细胞内质网应激
  • 批准号:
    6774686
  • 财政年份:
    2003
  • 资助金额:
    $ 43.22万
  • 项目类别:
Myocilin-induced ER Stress in Trabecular Meshwork Cells
肌纤蛋白诱导的小梁网细胞内质网应激
  • 批准号:
    6686910
  • 财政年份:
    2003
  • 资助金额:
    $ 43.22万
  • 项目类别:
VOLUME REGULATION IN CORNEAL ENDOTHELIUM
角膜内皮的体积调节
  • 批准号:
    6324068
  • 财政年份:
    1995
  • 资助金额:
    $ 43.22万
  • 项目类别:
VOLUME REGULATION IN CORNEAL ENDOTHELIUM
角膜内皮的体积调节
  • 批准号:
    2851741
  • 财政年份:
    1995
  • 资助金额:
    $ 43.22万
  • 项目类别:
VOLUME REGULATION IN CORNEAL ENDOTHELIUM
角膜内皮的体积调节
  • 批准号:
    6164684
  • 财政年份:
    1995
  • 资助金额:
    $ 43.22万
  • 项目类别:
VOLUME REGULATION IN CORNEAL ENDOTHELIUM
角膜内皮的体积调节
  • 批准号:
    6518537
  • 财政年份:
    1995
  • 资助金额:
    $ 43.22万
  • 项目类别:
VOLUME REGULATION IN CORNEAL ENDOTHELIUM
角膜内皮的体积调节
  • 批准号:
    6363138
  • 财政年份:
    1995
  • 资助金额:
    $ 43.22万
  • 项目类别:

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