Circulating and Urinary Microparticles as Markers of End-organ Damage in Hypertension

循环和尿液微粒作为高血压终末器官损伤的标志物

• 批准号: 9479262
• 负责人: Uta Erdbruegger
• 金额: $ 19.2万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-20 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9479262
• 关键词: Adrenal Gland Adenoma; Advisory Committees; Affect; Aftercare; Aldosterone; American; Angioplasty; Angiotensin II; Animal Experimentation; Animal Model; Animals; Antihypertensive Agents; Area; Attention; Basic Science; Biological; Biological Markers; Biology; Biometry; Blood Platelets; Blood Pressure; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cells; Characteristics; Clinic; Clinical; Clinical Research; Clinical Sciences; Clinical Trials Design; Collaborations; Committee Members; Data; Detection; Development; Development Plans; Diabetic Nephropathy; Diagnosis; Diagnostic; Diet; Disease; Dose; Early Diagnosis; Early Intervention; Early treatment; Enalapril; Endocrinology; Environment; Essential Hypertension; Etiology; European; Event; Excision; Exposure to; Fibromuscular Dysplasia; Flow Cytometry; Funding; Future; Goals; Guidelines; Human; Hydrochlorothiazide; Hypertension; Image; In Vitro; Inbred SHR Rats; Inflammation; Injury; Intervention; Interventional radiology; Investigation; Kidney; Kidney Diseases; Knowledge; Leukocytes; Malignant - descriptor; Measurement; Measures; Membrane; Mentored Patient-Oriented Research Career Development Award; Mentors; Methodology; Methods; Modeling; Mus; NG-Nitroarginine Methyl Ester; Nature; Nephrosclerosis; Nitric Oxide Synthetase Inhibitor; Organ; Parents; Patient Recruitments; Patients; Phase; Phenotype; Physicians; Physiology; Population Heterogeneity; Pre-Eclampsia; Preparation; Primary Hyperaldosteronism; Process; Prognostic Marker; Property; Proteinuria; Rattus; Renal Artery Stenosis; Research; Research Infrastructure; Research Personnel; Research Project Grants; Resistant Hypertension; Resources; Risk Factors; Role; Scientist; Secondary Hypertension; Secondary to; Severities; Societies; Sodium Chloride; Stress; Stroke; Symptoms; Techniques; Testing; Time; Training; Translational Research; Universities; Urine; Vasculitis; Vesicle; Virginia; Work; base; blood pressure regulation; candidate marker; career development; cell type; clinical biomarkers; endothelial dysfunction; experience; high salt diet; hypertension treatment; imaging modality; in vivo; kidney vascular structure; mouse model; novel; novel marker; novel strategies; patient oriented research; podocyte; pre-clinical; programs; public health relevance; response; skills; tool; urinary

 DESCRIPTION (provided by applicant): CANDIDATE: Dr. Erdbrügger is a nephrologist at the University of Virginia who has drawn on her training and experience in clinical and basic science to develop a research program focused on translational research. Her previous background and work on biomarkers for vascular damage in vasculitis, thrombotic microangiopathy, and preeclampsia has now evolved to her current focus on early detection of vascular damage in hypertension using microparticles (MPs) as the biological footprint. To this end, she seeks a K23 award to support 75% protected time to focus on using advanced image flow cytometry to carefully and rigorously delineate the characteristics of microparticle subtypes in different forms of hypertension in both human patients and rats. CAREER DEVELOPMENT: The long-term goal of Dr. Erdbrügger is to become an independently funded physician scientist in the field of biomarkers of vascular damage and disease. Through the outlined research plan, the candidate hopes to 1) become a well recognized expert within the area of biomarker research, specifically on circulating and urinary MPs, 2) enhance her basic research skills in advanced flow cytometry, whole animal physiology and vascular biology, and 3) enhance her skills and knowledge in clinical research and clinical trial design as a physician scientist. Dr. Erdbrügger strives to expand her research program beyond descriptive studies and use newly developed skills, knowledge, productive collaborations and data form ongoing studies to also define mechanistically the active/functional role of MPs in hypertension and endothelial dysfunction. The results from this proposal will be used in preparation for an R01 application that will be submitted in the latter phase of the K23 award. The career development plan includes didactic course work to equip Dr. Erdbrügger with advanced and comprehensive knowledge of flow cytometry, and conduct of patient oriented research and animal research. INSTITUTIONAL ENVIRONMENT: The University of Virginia offers an excellent environment for the proposed study. The readily available infrastructure for patient recruitment from the Kidney Clinic (for essential/resistant hypertension), the Endocrinology Clinic (for primary hyperaldosteronism (PHA)), the large referral base to Interventional Radiology (for renal vascular hypertension, including fibromuscular dysplasia (FMD)), and the expertise of investigators in the fields of basic research in Hypertension (Drs. Thu Le and Robert Carey, her primary co-mentors), in biostatistics (Dr. Jennie Ma, mentor) and advanced flow cytometry (Joanne Lannigan) together provide all the necessary resources, skills and support for successful execution of the proposed studies. RESEARCH PROJECT: This Mentored Patient-Oriented Research Career Development Award (K23) application seeks to establish the diagnostic role of circulating and urinary microparticles (MPs) in early or pre- clinical organ damage from specific forms of hypertension (HTN). MPs are a heterogeneous population of small membrane fragments shed from various cell types and carry specific markers of their parent cell. They have gained significant attention as potential novel biomarkers for endothelial dysfunction and vascular damage. However, these earlier studies of MPs have been mostly done in-vitro. The proposed study will be the first to look at MPs of endothelial origin in vivo, using a novel and more sensitive method of imaging flow cytometry Dr. Erdbrügger and Joanne Lannigan developed to detect MPs. In exciting preliminary data, Dr. Erdbrügger has found that most endothelial derived MPs rise in 2 weeks in mice with angiotensin II (Ang II) induced HTN and decrease after 4 weeks despite sustained HTN. In contrast, only leukocyte derived MPs increase over time and correlate best with severity of HTN. In Aim 1 we will test the hypothesis that specific subsets of MPs are released in spontaneous hypertensive rats (SHR) and the stroke prone SHR (SHRsp) before and after development of HTN, and that the levels of MPs subtypes change with the severity of HTN and after antihypertensive treatment. In addition, we will detect podocyte-derived MP in urine in these rats as an early marker for hypertensive damage in the kidneys. Dr. Erdbrügger also found that different types of endothelial derived MPs are significantly elevated in HTN induced by Ang II compared to that by L-NAME, a nitric oxide synthase inhibitor, suggesting different mechanism(s) of endothelial damage. In Aim 2 we will test the hypothesis that subtypes of MPs from patient with HTN due to essential HTN, fibromuscular dysplasia and PHA will be diagnosis-specific and will decrease after disease-specific intervention. We further hypothesize that the levels of MPs will decrease after intervention with angioplasty in FMD or surgical removal of adrenal adenoma in PHA. Podocyte derived MPs will also be detected as early markers of renal damage in these hypertensive patients. The knowledge gained from this project will reveal, in real time, the vascular response to hypertension. Our work will be the first step to define the footprint or consequence of the vascular damage from specific forms of HTN for future investigation to mechanistically delineate the exact nature of vascular injury.

 描述(由申请人提供)： 候选人：埃尔德鲁格博士是弗吉尼亚大学的一名肾病学家，她利用自己在临床和基础科学方面的培训和经验，开发了一个专注于转化性研究的研究项目。她以前的背景和在血管炎、血栓性微血管病和先兆子痫中血管损伤的生物标记物方面的工作现在演变为她目前的重点是使用微粒(MPS)作为生物足迹来早期检测高血压患者的血管损伤。为此，她寻求K23奖项，以支持75%的保护时间，专注于使用先进的图像流式细胞术，仔细而严格地描绘人类患者和大鼠不同形式高血压中微粒亚型的特征。 职业发展：埃尔德吕格博士的长期目标是成为血管损伤和疾病生物标记物领域的独立资助内科科学家。通过概述的研究计划，候选人希望1)成为生物标记物研究领域的知名专家，特别是循环和尿液MPS方面的专家；2)提高她在高级流式细胞术、全动物生理学和血管生物学方面的基本研究技能；3)作为一名内科科学家，提高她在临床研究和临床试验设计方面的技能和知识。埃尔德鲁格博士努力将她的研究项目扩展到描述性研究之外，并使用新开发的技能、知识、富有成效的合作和正在进行的研究中的数据来机械地定义MPS在高血压和内皮功能障碍中的积极/功能作用。这项提案的结果将用于准备R01申请，该申请将在K23奖项的后期阶段提交。职业发展计划包括授课课程工作，以使埃尔德布鲁格博士掌握先进而全面的流式细胞仪知识，以及开展以患者为导向的研究和动物研究。 制度环境：弗吉尼亚大学为拟议的研究提供了良好的环境。从肾脏诊所(针对原发性/顽固性高血压)、内分泌诊所(针对原发性醛固酮增多症(PHA))、庞大的介入放射科转诊基础(针对肾血管高压，包括纤维肌肉发育不良(FMD))，以及高血压基础研究领域的研究人员(乐清华博士和Robert Carey博士，是她的主要合作导师)、生物统计学(Ma博士，导师)和高级流式细胞术(Joanne Lannigan)等专业人员提供所有必要的资源、技能和支持，为成功进行拟议的研究提供了所有必要的资源、技能和支持。 研究项目：这项以患者为导向的研究职业发展奖(K23)申请旨在确定循环和尿液微粒(MPS)在特定形式高血压(HTN)早期或临床前器官损害中的诊断作用。MPS是从不同细胞类型脱落的小膜碎片的异质性群体，携带其母细胞的特定标记。它们作为潜在的内皮功能障碍和血管损伤的新型生物标志物已经引起了人们的极大关注。然而，这些早期对MPS的研究大多是在体外进行的。这项拟议的研究将首次在体内观察内皮来源的MPS，使用Erdrrügger博士和Joanne Lannigan为检测MPS而开发的一种新的、更灵敏的成像流式细胞术方法。在令人兴奋的初步数据中，Erdbrügger博士发现，在血管紧张素II(Ang II)诱导HTN的小鼠中，大多数内皮源性MPS在2周内上升，4周后下降，尽管HTN持续存在。相反，只有白细胞来源的MPS随着时间的推移而增加，并且与HTN的严重程度相关性最好。在目标1中，我们将验证以下假设：自发性高血压大鼠(SHR)和卒中易感自发性高血压大鼠(SHRsp)在HTN形成前后释放特定的MPS亚群，并且MPS亚型水平随着HTN的严重程度和降压治疗后的变化而变化。此外，我们将在这些大鼠的尿中检测到足细胞来源的MP，作为高血压肾脏损害的早期标志。埃尔德布鲁格博士还发现，与一氧化氮合酶抑制剂L-NAME相比，血管紧张素II诱导的HTN中不同类型的内皮来源MPS显著增加，这表明内皮损伤的机制(S)不同。在目标2中，我们将检验一种假设，即特发性HTN、纤维肌肉发育不良和PHA引起的HTN患者的MPS亚型将具有诊断特异性，并且在疾病特异性干预后将会减少。我们进一步假设，在FMD行血管成形术或在PHA行肾上腺腺瘤切除手术干预后，MPS水平将会降低。足细胞来源的MPS也将被检测为这些高血压患者肾脏损害的早期标志。从这个项目中获得的知识将实时揭示血管对高血压的反应。我们的工作将是确定特定形式的HTN造成的血管损伤的足迹或后果的第一步，以便将来从机制上描述血管损伤的确切性质。