Late/chronic corneal injury following threat chemical exposure
威胁化学品暴露后的晚期/慢性角膜损伤
基本信息
- 批准号:10676950
- 负责人:
- 金额:$ 45.6万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-01 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
Abstract
Exposure of Carbofuran (CF; a pesticide) and Chlorine (Cl2; a bleaching and warfare agent) to humans is a major
public health issue. Over 3 million people exposed to CF/Cl2 show high ocular morbidity. A major gap in
knowledge is lack of mechanistic data “how CF/Cl2 exposure causes corneal injury and vision loss”? We test a
novel hypothesis that mTORC1-mediated dysfunctional autophagosome formation and lysosomal biogenesis
are a dominant operating mechanism for corneal damage from exposure of these threat chemicals (CF/Cl2).
Autophagy and lysosomal biogenesis play a key role in corneal homeostasis and transparency maintenance.
Our hypothesis is based on a human-patient study identifying defective autophagy the cause of slow and
progressive corneal thinning and vision loss in keratoconus patients. Pilot studies performed with mice and donor
human corneas strongly supports our novel hypothesis. The main goal of this project is to test our hypothesis
employing highly rigorous approach using 2 threat chemicals (CF and Cl2) and 2 animal species (C57BL/6J mice
and New Zealand White rabbits) and applicability of postulated mechanism in human using donor human cornea
derived organ culture and primary cell culture models using two entirely independent but integrated specific aims.
Aim-1 defines clinical signs and underline mechanism of late/chronic corneal toxicity caused by CF exposure to
the eye using 3 sub-aims: (1a) records clinical signs and changes in the phenotype and density of corneal
epithelial, stromal keratocytes, and endothelial cells in CF +/- exposed eyes of live rabbits and mice in vivo every
two weeks interval with slit-lamp, HRT3-RCM confocal, Specular, and Spectralis optical coherence tomography
microscopy system until 6 months, (1b) defines the mechanism by analyzing autophagosomal and lysosomal
signature genes (ATGs, LC3, SQSTM1/p62, LAMP1, mTORC1, TFEB, & vATPase) in CF +/- exposed corneas
of 2 species collected at 1, 2, 4, and 6 months, and (1c) verifies applicability of postulated mechanism in human
using cadaver corneas. Aim-2 defines clinical symptoms and underline mechanism of late/chronic corneal
toxicity caused by Cl2 exposure to the eye using 3 sub-aims: (2a) records clinical signs and changes in the
phenotype and density of corneal epithelial, stromal keratocytes, and endothelial cells in Cl2 +/- eyes of live
rabbits and mice in vivo, (2b) elucidates Cl2-induced corneal damage by studying autophagosomal and
lysosomal signatures stated in aim-1b in Cl2 +/- corneas of 2 species, and (2c) verifies applicability of mechanism
in humans using control donor human corneas employing an experimental approach and techniques stated in
Aim-1a-c. With proposed studies, we expect to define start time, extent, and duration of symptoms after CF and
Cl2 exposure in live animals, role of mTORC1 mediated autophagic events in CF/Cl2 exposed corneas and
signature autophagosomal and lysosomal genes linked to CF/Cl2 mediated corneal toxicity. Successful
completion of studies is expected to fill many knowledge gaps and advance ocular counterACT field significantly.
抽象的
将碳氟烷(CF;农药)和氯(CL2;漂白和战争剂)暴露于人类是主要的
公共卫生问题。暴露于CF/CL2的300万人表现出高的眼部发病率。一个主要差距
知识是否缺乏机械数据“ CF/CL2暴露如何导致角膜损伤和视力丧失”?我们测试a
新的假设MTORC1介导的功能失调的自噬体形成和溶酶体生物发生
是暴露这些威胁化学物质(CF/CL2)因角膜损害的主要操作机制。
自噬和溶酶体生物发生在角膜稳态和透明度维持中起关键作用。
我们的假设是基于一项人类患者研究,确定自噬的缺陷是缓慢和的原因
圆锥角膜患者的进行性角膜稀疏和视力丧失。对小鼠和供体进行的试点研究
人角膜强烈支持我们的新假设。该项目的主要目标是检验我们的假设
使用2种威胁化学物质(CF和CL2)和2种动物(C57BL/6J小鼠)采用高度严格的方法
和新西兰白兔子)以及使用供体人角膜在人类中假定机制的适用性
使用两个完全独立但集成的特定目的的衍生器官培养和原代细胞培养模型。
AIM-1定义了由于CF暴露引起的临床体征和下划线机制
使用3个子Aims的眼睛:(1A)记录角膜表型和密度的临床体征和变化
CF +/-活体内的CF +/-暴露于活体内的CF +/-暴露眼睛中的上皮细胞和内皮细胞
缝隙灯,HRT3-RCM共焦,镜面和光谱光学相干断层扫描间隔两周间隔
显微镜系统直到6个月,(1B)通过分析自噬体和溶酶体来定义机制
签名基因(ATG,LC3,SQSTM1/P62,LAMP1,MTORC1,TFEB和VATPASE)在CF +/-暴露的角膜中
在1、2、4和6个月收集的2种,(1C)验证了人类假定机制的适用性
使用尸体角膜。 AIM-2定义临床症状和后期/慢性角膜的下划线机制
使用3个子IAMS导致CL2导致眼睛引起的毒性:(2a)记录临床体征和变化
角膜上皮,基质角膜细胞和内皮细胞的表型和密度
兔子和小鼠在体内,(2B)通过研究自噬体和
Cl2 +/-角膜中的AIM-1B中陈述的溶酶体特征,(2C)验证机制的适用性
在人类中,使用控制供体的人角膜采用实验方法和技术
AIM-1A-C。通过拟议的研究,我们期望CF和CF之后的开始时间,程度和症状持续时间
现场动物的CL2暴露,MTORC1介导的自噬事件在CF/CL2暴露角膜和
与CF/CL2介导的角膜毒性相关的签名自噬体和溶酶体基因。成功的
研究的完成预计将填补许多知识差距,并显着提高眼部抵抗场。
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)

暂无数据
数据更新时间:2024-06-01
Suneel Gupta的其他基金
Late/chronic corneal injury following threat chemical exposure
威胁化学品暴露后的晚期/慢性角膜损伤
- 批准号:1050799010507990
- 财政年份:2022
- 资助金额:$ 45.6万$ 45.6万
- 项目类别:
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