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Atheroprotective vs. Atherogenic Glycocalyx Mechanotransduction Mechanisms

动脉粥样硬化保护与致动脉粥样硬化糖萼机械转导机制

基本信息

批准号：
9768526
负责人：
Eno Essien Ebong
金额：
$ 16.02万
依托单位：
NORTHEASTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-04 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9768526
关键词：
Acute Adhesions Anatomy Aneurysm Animals Apolipoprotein E Atherosclerosis Award Biochemical Biological Biological Markers Biomedical Engineering Blood Vessels California Cardiovascular system Carotid Arteries Caveolae Cell Culture Techniques Cell Shape Cell physiology Cellular biology Cities Communication Connexins Core Protein Cytoskeleton Deacetylase Development Diagnosis Disease Electron Microscopy Endothelial Cells Endothelium Engineering Environment Enzymes Europe Event Faculty Fatty acid glycerol esters Foundations Freeze Substitution Freezing Functional disorder Future Gap Junctions Geometry Glycobiology Glycocalyx Glypican Goals Health Heparitin Sulfate Immunofluorescence Microscopy Impairment In Vitro Institutes Institution Interdisciplinary Study Knockout Mice Laboratories Lead Lesion Measures Mechanics Mediating Medical Medicine Membrane Mentored Research Scientist Development Award Mentors Microscopy Modeling Molecular Biology Molecular Target Morphology Mus Myocardial Infarction New York Nitric Oxide Nitric Oxide Synthase Operative Surgical Procedures Pathology Pattern Peripheral Vascular Diseases Positioning Attribute Prevention approach Production Regulation Relaxation Research Research Infrastructure Research Personnel Role Severities Signal Transduction Site Solid Stimulus Stroke Structure Surface Talents Techniques Technology Testing Thick Tissues Training Translating Transmission Electron Microscopy Uncertainty United States Universities Vascular Diseases Voice Work atherogenesis atheroprotective career cell behavior cell type cellular targeting college combat constriction endothelial dysfunction experience experimental study extracellular histological studies improved in vivo in vivo Model innovation mechanotransduction medical schools method development monolayer mouse model new therapeutic target novel diagnostics prevent professor programs response structural biology sulfotransferase syndecan tenure track theories tool transmission process

项目摘要

DESCRIPTION (provided by applicant): The K01 will facilitate Dr. Ebong's development of her independent research position as a tenure-track professor. Her research objective is to combine engineering with advanced microscopy, cell and molecular biology, and animal pathophysiology to elucidate endothelial cell (EC) glycocalyx (GCX) ultrastructure and its functional role in EC mechanotransduction and vascular function in health and atherosclerosis. With her background in core engineering theory and practice, and her solid interdisciplinary research experience that blends cardiovascular and cellular bioengineering with molecular biology, Dr. Ebong is highly qualified to carry out the Research Strategy and meet the Career Goals and Objectives. This award will enable her to expand her research, enhance its interpretation, and produce new discoveries. Dr. Ebong will be mentored by an interdisciplinary team that has broad expertise in bioengineering, in vitro and in vivo shear and mechanotransduction experiments, in vivo modeling of vascular pathology, glycobiology, microscopy, anatomy and structural biology, and molecular biology. The make-up of this team will provide her with an extensive network of techniques, facilities, and research institutions. The mentored activities proposed for this K01 program will be primarily conducted at Northeastern University and performed in Dr. Ebong's laboratory. Faculty and facilities of Northeastern (Drs. Ruberti, Khaw, and Hancock), The City College of New York (Dr. Tarbell), Albert Einstein College of Medicine (Mr. Macaluso), Emory University School of Medicine and Georgia Institute of Technology (Dr. Jo), Temple University School of Medicine (Dr. Rizzo), and University of California at San Diego (Dr. Esko) will also support Dr. Ebong's training. Atherosclerosis occurs at blood vessel sites, such as branches, where unstable (disturbed) flow makes the endothelial cell (EC) layer dysfunctional. Healthy tissue lines straight blood vessels where streamlined (uniform) flow permits normal EC function. The mechanisms by which flow alters EC function to prevent or promote atherosclerosis remain unclear. Defining these mechanisms is the primary focus of Dr. Ebong's research program. The K01 research strategy proposed by Dr. Ebong and her team is to study the structure and function of a prime EC mechanotransducer candidate-the surface glycocalyx (GCX)-which directly senses flow, can transmit force via the cytoskeleton to various biologically active cellulr sites, and sheds in atherosclerosis. GCX is essential for flow conversion to EC functions including nitric oxide (NO) release, cytoskeleton organization, gap junction communication, and cell shape that are abnormal in atherosclerosis. Dr. Ebong has already shown that flow induces vasoregulatory EC-type NO synthase (eNOS) activation, but only in the presence of the heparan sulfate (HS) glypican-1 (GPC-1) component of the EC GCX. Her work has revealed that flow-induced EC remodeling relies on the HS syndecan-1 (SDC-1) component of the GCX. Using rapid freezing/freeze substitution (RF/FS) transmission electron microscopy (TEM), she is currently defining the EC GCX ultrastructure and its changes due to cellular origin and the biochemical and flow environment. During the period of the K01 award, Dr. Ebong and her team will advance this work by testing the hypothesis that EC respond differently to uniform and disturbed flow through dynamic changes in GCX ultrastructure (Aim 1), which trigger the caveolae and cytoskeleton (and subsequently, the gap junctions and basal matrix) to differentially activate EC signaling and remodeling events (Aim 2) that lead to vascular health or disease (Aim 3). This hypothesis will be tested using cultured EC with intact or manipulated GCX, which are subjected to atheroprotective and atherogenic flow conditions that are replicated in vitro using a parallel plate flow chamber. Mouse models of GCX component deletion, acute disturbed flow, endothelial and vascular dysfunction, and atherosclerosis will also be employed. Flow-induced GCX thickness, morphology, and subcomponent content and organization will be assessed. Flow- and GCX-regulation of EC signaling and remodeling events such as eNOS activation and NO production, connexin-specific gap junction signaling, and remodeling of cell shape and basal adhesions will be examined. GCX component-specific involvement in EC- dependent vasoregulation, the development of robust atherosclerosis, and the determination of lesion complexity will also be studied. The team expects to identify GCX components that are biomarkers of atherosclerosis. The findings of this research will be essential for engineering new diagnostics and therapeutics that target the EC GCX to combat atherosclerosis. Dr. Ebong is talented, the mentoring and research team is experienced and interdisciplinary, and the research strategy is exciting and innovative. Without a doubt, Dr. Ebong will emerge from the K01 as an independent investigator with a unique identity, a wide-range of powerful research tools, a robust research infrastructure, and a voice in high-level discourse on GCX-related approaches to the prevention, diagnosis, and treatment of atherosclerosis. (End of Abstract)

描述（由申请人提供）：K 01将促进Ebong博士作为终身教授的独立研究职位的发展。她的研究目标是将联合收割机工程与先进的显微镜、细胞和分子生物学以及动物病理生理学相结合，以阐明内皮细胞（EC）糖萼（GCX）的超微结构及其在健康和动脉粥样硬化中EC机械转导和血管功能中的功能作用。凭借她在核心工程理论和实践方面的背景，以及她将心血管和细胞生物工程与分子生物学相结合的坚实的跨学科研究经验，Ebong博士完全有资格实施研究战略并实现职业目标和目的。这个奖项将使她能够扩大她的研究，提高其解释，并产生新的发现。 Ebong博士将由一个跨学科团队指导，该团队在生物工程，体外和体内剪切和机械转导实验，血管病理学，糖生物学，显微镜，解剖学和结构生物学以及分子生物学的体内建模方面具有广泛的专业知识。该团队的组成将为她提供广泛的技术，设施和研究机构网络。K 01计划的指导活动将主要在东北大学进行，并在Ebong博士的实验室进行。东北大学（Ruberti、Kestival和汉考克博士）、纽约城市学院（Tarbell博士）、阿尔伯特·爱因斯坦医学院（Macaluso先生）、埃默里大学医学院和格鲁吉亚理工学院（Jo博士）、坦普尔大学医学院（Rizzo博士）和加州大学圣地亚哥分校（Esko博士）的教师和设施也将支持Ebong博士的培训。动脉粥样硬化发生在血管部位，例如分支，其中不稳定（受干扰）的流动使内皮细胞（EC）层功能失调。健康的组织排列在直的血管中，流线型（均匀）流动允许正常的EC功能。流动改变EC功能以预防或促进动脉粥样硬化的机制尚不清楚。确定这些机制是Ebong博士研究计划的主要重点。Ebong博士和她的团队提出的K 01研究策略是研究一种主要的EC机械转换器候选者-表面糖萼（GCX）的结构和功能-它直接感知流量，可以通过细胞骨架将力传递到各种生物活性细胞位点，并在动脉粥样硬化中脱落。GCX对于血流转换为EC功能至关重要，包括一氧化氮（NO）释放、细胞骨架组织、间隙连接通讯和动脉粥样硬化中异常的细胞形状。Ebong博士已经表明，流动诱导血管调节EC型NO合酶（eNOS）激活，但仅在EC GCX的硫酸乙酰肝素（HS）磷脂酰肌醇蛋白聚糖-1（GPC-1）组分存在的情况下。她的研究表明，血流诱导的EC重塑依赖于GCX的HS syndecan-1（SDC-1）组分。使用快速冷冻/冷冻替代（RF/FS）透射电子显微镜（TEM），她目前正在定义EC GCX超微结构及其变化，由于细胞起源和生物化学和流动环境。在K 01奖期间，Ebong博士和她的团队将通过测试EC通过GCX超微结构的动态变化（Aim 1）对均匀和扰动流做出不同反应的假设来推进这项工作，GCX超微结构的动态变化触发了细胞膜小窝和细胞骨架（随后，差距连接和基底基质）以差异性地激活EC信号传导和重塑事件（目的2），从而导致血管健康或疾病（目的3）.该假设将使用具有完整或操作的GCX的培养EC进行测试，其经受使用平行板流动室在体外复制的动脉粥样硬化保护和致动脉粥样硬化流动条件。还将采用GCX组分缺失、急性血流紊乱、内皮和血管功能障碍以及动脉粥样硬化的小鼠模型。将评估流动诱导的GCX厚度、形态以及子组分含量和组织。将检查EC信号传导和重塑事件（如eNOS活化和NO产生、连接蛋白特异性间隙连接信号传导以及细胞形状和基底粘附的重塑）的流动和GCX调节。还将研究GCX组分特异性参与EC依赖性血管调节、稳健动脉粥样硬化的发展以及病变复杂性的确定。该团队希望确定GCX成分是动脉粥样硬化的生物标志物。这项研究的结果对于设计新的诊断和治疗方法至关重要，这些方法针对EC GCX以对抗动脉粥样硬化。 Ebong博士才华横溢，指导和研究团队经验丰富，跨学科，研究策略令人兴奋和创新。毫无疑问，Ebong博士将从K 01中脱颖而出，成为一名独立的研究者，拥有独特的身份，广泛的强大研究工具，强大的研究基础设施，以及在GCX相关方法的高级别话语中的声音，以预防，诊断和治疗动脉粥样硬化。(End摘要）

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Diosmin and its glycocalyx restorative and anti-inflammatory effects on injured blood vessels.

地奥司明及其糖萼对受损血管的恢复和抗炎作用。

DOI：
10.1096/fj.202200053rr
发表时间：
2022
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
0
作者：
Mitra,Ronodeep;Nersesyan,Alina;Pentland,Kaleigh;Melin,MMark;Levy,RobertM;Ebong,EnoE
通讯作者：
Ebong,EnoE

Glycocalyx in Atherosclerosis-Relevant Endothelium Function and as a Therapeutic Target.