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Mechanisms of Endothelial Cell Dysfunction in Critically Ill Children

危重儿童内皮细胞功能障碍的机制

基本信息

批准号：
10703207
负责人：
RICHARD W PIERCE
金额：
$ 13.18万
依托单位：
YALE UNIVERSITY
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：
2019-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10703207
关键词：
Adherens Junction Bioinformatics Biological Assay Biological Models Biology Blood Blood Vessels Blood capillaries CRISPR/Cas technology Candidate Disease Gene Capillary Endothelial Cell Capillary Leak Syndrome Capillary Permeability Cardiopulmonary Cell Culture Techniques Cell Line Cell Separation Cells Cessation of life Child Childhood Clinical Collecting Cell Critical Care Critical Illness Critically ill children Data Dermal Deterioration Development Edema Electrical Resistance Endothelial Cells Endothelium Etiology Event Extramural Activities Failure Fellowship Functional disorder Funding GTPase-Activating Proteins Gene Expression Gene Mutation Genes Genetic Genetic Techniques Genetic Transcription Goals Guanine Nucleotide Exchange Factors Guanosine Triphosphate Phosphohydrolases Human Immunologic Techniques Immunology Individual Inflammatory Jordan Laboratories Liquid substance Lung Mediating Mediator Medicine Mentors Mentorship Methodology Methods Modeling Modification Monomeric GTP-Binding Proteins Morbidity - disease rate Multiple Organ Failure Mutation Nutrient Organ Pathologic Pathway interactions Patients Permeability Play Process Protocols documentation Regulation Research Research Methodology Research Personnel Research Project Grants Research Support Resolution Resources Role Scientist Signal Pathway Signal Transduction Skin Syndrome TNF gene Testing Tight Junctions Time Titrations Training Umbilical vein Vascular Endothelial Cell Vascular Permeabilities Venous Work candidate identification cell type clinically significant cytokine endothelial dysfunction experience gene product improved instructor interstitial knock-down lung microvascular endothelial cells medical schools mortality multidisciplinary novel novel therapeutic intervention overexpression pediatric patients pharmacologic prevent professor programs response rho GTP-Binding Proteins single-cell RNA sequencing skills symposium targeted treatment therapy development tool transcriptome

项目摘要

Project Summary Candidate. I am an Instructor in pediatric critical care medicine at Yale School of Medicine and will be promoted to Assistant Professor with academic promotion per Yale School of Medicine's Clinician Scholar track in July 2018. My K08 application will allow me to acquire additional mentored research experience so that I may become an independent investigator with expertise in endothelial cell signaling and its disruption in critically ill children. This research will build on my fellowship training that focused on the signals that regulate changes in vascular permeability and their associated clinical consequences and will further develop my laboratory skills required to successfully conduct vascular research, such as genetic modification of human cells, interrogation of intracellular signaling pathways, and bioinformatic analysis. I will take graduate courses on vascular biology, bioinformatics, and immunology research methods and will participate in national conferences. I have an outstanding mentor, Dr. Jordan Pober, a world-class vascular biologist, along with advisors Dr. Mustafa Khokha, expert in genetics, and Dr. Vince Faustino, expert biostatistician and clinical trialist. This multidisciplinary mentorship team, along with the resources available through the VBT program at Yale, will allow me to develop the necessary skills to function as an extramurally funded clinician scientist focused on improving the care of critically ill children. Research Project. Endothelial cells (ECs) actively regulate vessel permeability that is essential for organ function and patient survival. During cardiopulmonary failure, loss of EC permselectivity results in capillary leak that contributes to morbidity and mortality in children. The unique regulation of the signaling events that produce permeability changes in capillary EC is largely unknown. Likewise, how critical illness induces EC dysfunction remains unknown, due in large part to our inability to directly assess EC changes in critically ill patients. I recently demonstrated the importance of the regulation of the small GTPase RhoB in a pediatric patient with systemic capillary leak syndrome caused by a single gene mutation. In Aim 1, I test the hypothesis that pathological capillary permeability is regulated by small GTPases and that these pathways are influenced by transcriptional changes induced by inflammatory cytokines. I will interrogate intracellular signaling pathways in capillary ECs cultured from different organs (skin and lung) to determine the effect of their modulation on trans-endothelial electrical resistance. In Aim 2, I will test the hypothesis that ECs undergo transcriptional changes in response to critical illness. I will analyze the entire transcriptome of individual venous ECs collected directly from critically ill children using single cell RNA sequencing. I will assess the functions of identified candidate gene products using pharmacologic, genetic, and immunologic techniques to manipulate and analyze their effect on the intracellular signaling pathways that control the initiation and resolution of capillary leak. Better understanding the pathways involved in the development and resolution of capillary leak is the first step in developing therapies for this common condition associated with serious morbidity and mortality.

项目摘要候选人。我是耶鲁医学院的一名儿科重症监护医学讲师，我将被提升 7月耶鲁医学院临床医生奖学金跟踪到助理教授和学术晋升 2018年。我的K08申请将允许我获得更多的指导研究经验，这样我就可以成为一位在危重儿童的内皮细胞信号及其干扰方面具有专业知识的独立研究员。这项研究将建立在我的研究员培训的基础上，该培训侧重于调节血管变化的信号渗透性及其相关的临床后果，并将进一步发展我的实验室技能所需的成功地进行血管研究，如人类细胞的基因改造，细胞内的询问信号通路和生物信息学分析。我将选修血管生物学、生物信息学、和免疫学研究方法，并将参加国家会议。我有一位杰出的导师，世界级血管生物学家乔丹·波伯博士和遗传学专家穆斯塔法·霍卡博士的顾问，以及文斯·福斯蒂诺博士，他是生物统计学家和临床试验专家。这个多学科的指导团队，以及利用耶鲁大学VBT项目提供的资源，我将能够发展必要的技能作为一名医疗外资助的临床科学家，专注于改善危重儿童的护理。研究项目。血管内皮细胞(ECs)主动调节对器官至关重要的血管通透性功能和患者生存。在心肺衰竭期间，EC通透性丧失会导致毛细血管渗漏这导致了儿童的发病率和死亡率。对产生的信号事件的独特调节毛细血管内皮细胞的通透性变化在很大程度上是未知的。同样，危重疾病如何导致EC功能障碍仍然未知，很大程度上是因为我们无法直接评估危重患者EC的变化。我最近证明调节小GTP酶RhoB在系统性红斑狼疮儿童患者中的重要性由单基因突变引起的毛细血管渗漏综合征。在目标1中，我测试了病理性的假设毛细血管通透性由小的GTP酶调节，这些途径受转录的影响炎性细胞因子诱导的变化。我将询问毛细血管内皮细胞的细胞内信号通路从不同器官(皮肤和肺)培养，以确定它们对跨内皮细胞的调节作用电阻。在目标2中，我将测试内皮细胞经历转录变化以响应得了重病。我将分析直接从危重病人身上收集的单个静脉内皮细胞的全部转录组。儿童使用单细胞RNA测序。我将评估已确定的候选基因产物的功能药理学、遗传学和免疫学技术来操纵和分析它们对细胞内的影响控制毛细管渗漏的开始和解决的信号通路。更好地理解这些途径参与开发和解决毛细血管渗漏是开发治疗方法的第一步与严重的发病率和死亡率相关的常见情况。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Relevance of Microvascular Flow Assessments in Critically Ill Neonates and Children: A Systematic Review.

DOI：
10.1097/pcc.0000000000002201
发表时间：
2020-04
期刊：
Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies
影响因子：
0
作者：
通讯作者：

A retrospective cohort analysis of the Yale pediatric genomics discovery program.

DOI：
10.1002/ajmg.a.62918
发表时间：
2022-10
期刊：
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
影响因子：
2
作者：
Al-Ali, Samir;Jeffries, Lauren;Faustino, E. Vincent S.;Ji, Weizhen;Mis, Emily;Konstantino, Monica;Zerillo, Cynthia;Jiang, Yong-hui;Spencer-Manzon, Michele;Bale, Allen;Zhang, Hui;McGlynn, Julie;McGrath, James M.;Tremblay, Thierry;Brodsky, Nina N.;Lucas, Carrie L.;Pierce, Richard;Deniz, Engin;Khokha, Mustafa K.;Lakhani, Saquib A.
通讯作者：
Lakhani, Saquib A.

Integrated Analysis of Tracheobronchial Fluid from Before and After Cardiopulmonary Bypass Reveals Activation of the Integrated Stress Response and Altered Pulmonary Microvascular Permeability.

DOI：
10.59249/kfyz8002
发表时间：
2023-03
期刊：
The Yale journal of biology and medicine
影响因子：
0
作者：
Habet V;Li N;Qi J;Peng G;Charkoftaki G;Vasiliou V;Sharma L;Pober JS;Dela Cruz C;Yan X;Pierce RW
通讯作者：
Pierce RW

Methylene Blue for Refractory Shock in Children: A Systematic Review and Survey Practice Analysis.