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RHO-ASSOCIATED KINASE-DEPENDENT CYTOSKELETAL AND TIGHTJUNCTION DYSREGULATION IN NECROTIZING ENTEROCOLITIS

坏死性小肠结肠炎中 RHO 相关激酶依赖性细胞骨架和紧密连接失调

基本信息

批准号：
10093948
负责人：
Catherine Jane Hunter
金额：
$ 6.53万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10093948
关键词：
Actins Actomyosin Affect Animal Model Antibiotics Apoptosis Binding Cell Culture Techniques Cell Death Cell Line Cell physiology Characteristics Childhood Clinical Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cytoskeleton Data Disease Emergency Situation Enterocytes Epithelial Epithelium Event Excision Functional disorder Future Goals Health Human Hypoxia In Vitro Infant Inflammation Inflammatory Intervention Intestines Knowledge Lipopolysaccharides Location Mediating Medical Mission Modeling Molecular Mucous Membrane Necrosis Necrotizing Enterocolitis Neonatal Intensive Care Units Newborn Infant Operative Surgical Procedures Outcome Oxidative Stress Pathogenesis Pathology Pathway interactions Patients Pattern Permeability Pharmacology Prevention strategy Process Production Protein Kinase Protein-Serine-Threonine Kinases Proteins Public Health Rattus Research Rest Rho-associated kinase Risk Factors Role Sampling Signal Pathway Signal Transduction Specimen Stress Structure Surgeon TLR4 gene Testing Therapeutic Therapeutic Intervention Tight Junctions Time Tissues United States National Institutes of Health Work clinically relevant cytokine feeding gastrointestinal genetic approach human disease human mortality improved improved outcome in vivo in vivo Model innovation insight intestinal barrier intestinal epithelium microbial colonization nature therapy novel novel therapeutic intervention premature preservation prevent protein distribution protein expression pup response rho targeted treatment treatment strategy

项目摘要

PROJECT SUMMARY/ ABSTRACT: Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency of newborns, and affects 7% of patients admitted to a neonatal intensive care unit. Despite years of research there is a gap in the understanding of the underlying pathophysiology of disease, and a lack of novel therapeutic approaches. Rho kinases (ROCK) are serine/ threonine kinases and are involved in multiple cellular processes including regulating tight junction function, actin cytoskeleton contraction, inflammatory cytokines and cell death. We and others, have previously demonstrated the relevance of these pathways to the pathophysiology of NEC. The objectives of this R03 proposal are to define mechanism(s) of ROCK activation, identify molecular pathways targeted by ROCK during experimental NEC and to determine the mechanisms by which ROCK inhibition limits NEC progression. The central hypothesis is that oxidative stress and LPS induce ROCK activation, resulting in cytoskeletal contraction and tight junction degradation that enhances mucosal and systemic inflammation and epithelial apoptosis. If this hypothesis is correct then ROCK inhibition will be protective against these effects and NEC. To test this hypothesis, we will examine the effects of signaling through ROCK pathway on tight junction proteins, epithelial permeability, inflammation and apoptosis during experimental NEC. The objective of this application is to define the ROCK-mediated molecular interactions that direct epithelial function during NEC. These studies will have great power since they will be performed in vitro, in enteroids, and in vivo models of NEC as well as in human intestinal samples from infants with and without NEC. We will determine whether inhibition of the ROCK pathway (by pharmacological and genetic approaches) can stabilize tight junctions and minimize inflammation, decrease cell death, and influence the outcomes and survival in experimental NEC. These findings will build upon my current studies, and have a significant positive impact on human health by providing a new understanding of the mechanisms governing epithelial intestinal barrier function during NEC.

项目总结/摘要：坏死性小肠结肠炎（NEC）是新生儿最常见的胃肠道急症，影响7%的新生儿新生儿重症监护室收治的患者。尽管经过多年的研究，疾病的潜在病理生理学，以及缺乏新的治疗方法。Rho激酶（ROCK）是丝氨酸/苏氨酸激酶，参与多种细胞过程，包括调节紧密连接功能、肌动蛋白细胞骨架收缩、炎性细胞因子和细胞死亡。我们和其他人，以前证明了这些途径与NEC病理生理学的相关性。本R 03的目标建议是定义ROCK激活的机制，鉴定ROCK在激活过程中靶向的分子途径，实验NEC和确定ROCK抑制限制NEC进展的机制。的中心假设是氧化应激和LPS诱导ROCK激活，导致细胞骨架收缩以及增强粘膜和全身炎症和上皮细胞凋亡的紧密连接降解。如果这假设是正确的，那么ROCK抑制将保护免受这些作用和NEC。为了验证这一假设，我们将研究通过ROCK途径对紧密连接蛋白，上皮细胞，在实验性NEC期间的渗透性、炎症和凋亡。本申请的目的是定义 ROCK介导的分子相互作用在NEC期间指导上皮功能。这些研究将因为它们将在体外、肠样组织和NEC的体内模型以及人体中进行，来自患有和不患有NEC的婴儿的肠样品。我们将确定是否抑制ROCK通路 (by药理学和遗传学方法）可以稳定紧密连接并使炎症最小化，减少炎症，细胞死亡，并影响实验NEC的结果和生存。这些发现将建立在我的目前的研究，并通过提供对人类健康的新认识， NEC期间控制上皮肠屏障功能的机制。