ROCK, tight junctions and prematurity in the pathogenesis of necrotizing enterocolitis and neonatal sepsis.

坏死性小肠结肠炎和新生儿败血症发病机制中的 ROCK、紧密连接和早产。

基本信息

批准号：
10659615
负责人：
Catherine Jane Hunter
金额：
$ 52.81万
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：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10659615
关键词：
12 year old Accounting Actins Affect Agonist Apoptosis Attenuated Cause of Death Cell Death Cell physiology Cessation of life Clinical Cyclic AMP-Dependent Protein Kinases Cytoskeleton Data Development Disease E-Cadherin Early Intervention Endocytosis Enterocytes Epithelial Cells Epithelium Event Excision Experimental Models Functional disorder Future Gestational Age Health Homeostasis Hospitalization Human Immune Impairment Infant Inflammation Inflammatory Injury Intercellular Junctions Intervention Intestinal Diseases Intestines Knockout Mice Knowledge Mediating Medical Mission Molecular Mucositis Mucous Membrane Mus Necrotizing Enterocolitis Neonatal Neonatal Intensive Care Units Newborn Infant Organ Organoids Outcome Pathogenesis Pathway interactions Patient Admission Patients Pattern Permeability Predisposition Premature Infant Prevention strategy Process Protein Kinase Protein-Serine-Threonine Kinases Proteins Public Health Regulation Research Rho-associated kinase Sampling Sepsis Signal Transduction Specimen Testing Therapeutic Intervention Tight Junctions Tissues United States National Institutes of Health Work caveolin 1 cytokine defined contribution feeding genetic approach human disease human mortality improved in vivo in vivo evaluation insight intestinal barrier intestinal epithelium microbial microbial colonization neonatal sepsis neonate occludin pharmacologic premature prevent protein expression protein function repaired response restoration rho systemic inflammatory response targeted treatment therapeutically effective therapy development translational potential treatment strategy

项目摘要

ABSTRACT: Necrotizing enterocolitis (NEC) is a deadly disease of the newborn that affects 7% of patients admitted to the neonatal intensive care unit and is a leading cause of gram negative, neonatal sepsis. Sepsis is the second major cause of death among neonates, accounting for one million global deaths per year. Although we have made progress understanding the effect of maternal colonization patterns on neonatal sepsis, there is a gap in the understanding of the regulatory processes that regulate intestinal barrier function that contribute to susceptibility to sepsis. Indeed, the intestine is the largest immune organ in the body and is responsible for maintaining a barrier to the microbial world within its lumen. Therefore, it is a high priority for the development of medical interventions to prevent and treat neonatal sepsis. 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 found that Rho-associated protein kinase (ROCK) is activated during NEC, and inhibition of ROCK confers protection against intestinal barrier injury and disruption of normal TJ homeostasis. Our data suggest that TJ regulation, intestinal barrier function and apoptosis are regulated by a ROCK dependent, caveolin-1 mediated pathway. Furthermore, we have identified differences in TJ subcellular distribution and caveolin-1 both in patients with and without sepsis and NEC, and in those of different gestational ages. The objective of our proposed study is to define the mechanism by which barrier loss occurs in NEC and to leverage this in order to understand the potential of epithelial-specific ROCK inhibition in preventing NEC and neonatal sepsis. Our central hypothesis is that the response of the intestinal barrier in premature infants to injury is altered and is characterized by changes in epithelial ROCK signaling, aberrant TJ regulation, increased mucosal and systemic inflammation, sepsis and epithelial cell death. We will test this hypothesis by determining whether inhibition of TJ protein expression and redistribution or caveolin-1-mediated endocytosis prevent paracellular permeability increases, mucosal and systemic inflammatory responses, and epithelial cell death in experimental sepsis and NEC. The use of intestinal organoids generated from human infants and from ROCK and caveolin-1 knockout mice, will provide tremendous translational power and allow us to probe epithelial functions at molecular, cellular, tissue, and organismal levels. Using pharmacological and genetic approaches, we will determine if and how TJ responsiveness and ROCK signaling increases cell death to worsen outcomes in premature infants and whether our interventions prevent or induce sepsis. These findings have a significant positive impact on human health by providing a new understanding of the mechanisms governing epithelial intestinal barrier function of the premature infant during NEC and neonatal sepsis.

抽象的：坏死性小肠结肠炎（NEC）是新生儿的致命疾病，影响7％的患者接受新生儿重症监护病房，是革兰氏阴性，新生儿败血症的主要原因。败血症是第二个新生儿中的主要死亡原因，每年全球死亡100万。虽然我们有取得了了解，了解母体定植模式对新生儿败血症的影响，存在差距对调节肠道屏障功能的调节过程的理解，这有助于对败血症的敏感性。确实，肠道是体内最大的免疫器官，负责在其管腔内保持对微生物世界的障碍。因此，这是发展的重点预防和治疗新生儿败血症的医疗干预措施。 Rho激酶（岩石）是丝氨酸/苏氨酸激酶并参与多个细胞过程，包括调节紧密连接功能，肌动蛋白细胞骨架收缩，炎症细胞因子和细胞死亡。我们发现与Rho相关的蛋白激酶（岩石）是在NEC期间被激活，抑制岩石赋予保护防止肠道屏障和破坏正常的TJ稳态。我们的数据表明，TJ调节，肠道屏障功能和凋亡是由依赖岩石的小窝蛋白-1介导的途径调节。此外，我们已经确定了有或没有败血症和NEC的患者，以及不同的妊娠年龄。我们提出的研究的目的是定义障碍损失的机制发生在NEC中，并利用这一点，以了解上皮特异性岩石抑制的潜力预防NEC和新生儿败血症。我们的中心假设是肠道屏障的反应过早的受伤婴儿发生了变化，其特征是上皮信号传导变化，异常TJ 调节，粘膜和全身性炎症，败血症和上皮细胞死亡。我们将测试这个通过确定抑制TJ蛋白表达和重新分布或小窝蛋白1介导的假设内吞作用可预防细胞细胞透性的渗透性增加，粘膜和全身性炎症反应，以及实验性败血症和NEC中的上皮细胞死亡。使用人类产生的肠癌婴儿以及岩石和小窝1敲除小鼠，将提供巨大的翻译能力，并允许我们探测分子，细胞，组织和生物水平的上皮功能。使用药理和遗传方法，我们将确定TJ反应性和岩石信号是否会增加细胞死亡为了使早产儿的结局恶化，以及我们的干预措施预防还是诱导败血症。这些发现通过提供对机制的新理解，对人类健康产生重大积极影响 NEC和新生儿败血症期间婴儿的上皮肠屏障功能。