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Mechanisms driving endothelial angiopoietin-2 expression and vascular dysfunction during pediatric sepsis

小儿脓毒症期间内皮血管生成素 2 表达和血管功能障碍的驱动机制

基本信息

批准号：
10347958
负责人：
Robert P Richter
金额：
$ 18.82万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-10 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10347958
关键词：
Adenosine Monophosphate Angiopoietin-2 Attenuated Automobile Driving Benchmarking Biological Markers Biology Blood Vessels Career Mobility Cell surface Cells Cessation of life Child Childhood Clinical Clinical Research Data Development Development Plans Endothelial Cells Endothelium Flow Cytometry Fostering Functional disorder Funding Glycocalyx Goals Health Heparitin Sulfate Hospital Mortality Hour Human Impairment In Vitro Injury Institution International Knowledge Lead Lung Measures Mediating Mentors Mentorship Modeling Modern Medicine Morbidity - disease rate Mus Observational Study Organ Outcome Pathology Pathway interactions Permeability Physicians Plasma Process Property Protein Kinase Research Research Training Resources Role STK11 gene Scientist Sepsis Signal Pathway Signal Transduction Surface TIE-2 Receptor Techniques Testing Therapeutic Training Training Programs Translational Research United States National Institutes of Health Vascular Diseases Vascular Permeabilities Work autocrine career career development clinical translation electric impedance endothelial dysfunction exosome gain of function in vivo mRNA Expression monolayer mortality nanoparticle neutralizing antibody novel novel therapeutics organ injury paracrine programs promoter prospective protein expression septic shear stress small molecule therapeutic target translational scientist vascular endothelial dysfunction vascular injury

项目摘要

This K08 proposal describes a 5-year research training program that will prepare the candidate for a career as an independent, NIH-funded translational scientist focused on mechanisms driving sepsis-mediated vascular disease. The scientific premise for the aims is that vascular endothelial dysfunction is a key driver of organ injury in pediatric sepsis. Morbidity and mortality remain unacceptably high in pediatric sepsis despite advances in modern medicine, principally due to knowledge gaps in the mechanisms driving vascular disease during sepsis. Endothelial cell-derived angiopoietin-2 (Ang-2) has emerged as a critical promoter of vascular injury and organ impairment in sepsis through its antagonism of the endothelial Tie2 receptor. Plasma Ang-2 levels are significantly elevated in children with sepsis and are associated with measures of organ injury and outcomes. Preliminary data suggest that heparan sulfate cleavage from the surface glycocalyx of flow conditioned primary human lung microvascular endothelial cells promotes Ang-2 expression, implicating a novel paradigm by which Ang-2 is upregulated in sepsis. Preliminary data and prior work also suggest that inactivation of liver kinase B1 (LKB1) and downstream adenosine-monophosphate-activated protein kinase (AMPK) may be integral in this process. Further, the candidate discovered that Ang-2 is bound to the surface of exosomes isolated from plasma of septic children, suggesting that exosomal Ang-2 may significantly contribute to vascular disease and organ injury during sepsis. Together, these data support the novel mechanistic hypothesis that enzymatic heparan sulfate erosion from the endothelial glycocalyx during pediatric sepsis upregulates expression of Ang-2 that, when bound to exosomes, has potent vascular destabilizing effects. To test this hypothesis, in vitro, ex vivo, and clinical studies will be performed in the following two aims. Aim 1: Test the hypothesis that glycocalyx heparan sulfate erosion increases Ang-2 expression from flow conditioned human lung microvascular endothelial cells via attenuated LKB1 activity and downstream AMPK pathway signaling. Aim 2: Test the hypothesis that exosomal Ang-2 (a) is biomarker for organ injury and clinical outcomes in pediatric sepsis and (b) promotes endothelial permeability via Tie2 receptor antagonism. Harnessing the combined expertise of the candidate’s mentoring team and utilizing the wealth of resources available at the candidate’s institution, the candidate will train in advanced translational science techniques germane to the completion of these aims, including microvascular flow modeling, nanoparticle tracking analysis and characterization with flow cytometry, and electric cell-substrate impedance sensing. The proposed research program has defined benchmarks that will facilitate the candidate’s career advancement and will culminate in the submission of an R01 to continue uncovering the mechanisms driving vascular disease in pediatric sepsis that will foster the discovery of novel therapeutics.

这份K08提案描述了一个为期5年的研究培训计划，将为候选人的职业生涯做准备