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: 9269251
• 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/9269251
• 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; 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：Erdbrügger博士是弗吉尼亚大学的肾脏科医生，她借鉴了她在临床和基础科学领域的培训和经验，以开发着一项针对转化研究的研究计划。她以前的背景和对生物标志物的血管损伤，血栓形成微型血管病和先兆子痫的血管损伤的工作已经演变为她目前对使用微粒（MPS）在高血压（MPS）中作为生物学足迹的早期发现的重点。为此，她寻求K23奖，以支持75％的保护时间，以专注于使用先进的图像流式细胞仪，以仔细而严格地描绘人类和大鼠中不同形式的高血压的微粒亚型的特征。 职业发展：Erdbrügger博士的长期目标是成为血管损伤和疾病生物标志物领域的独立物理科学家。通过概述的研究计划，候选人希望1）成为生物标志物研究领域的知名专家，特别是关于循环和尿尿MPS，2）增强她在先进的流式细胞仪，全动物生理学和血管生物学和血管生物学方面的基础研究技能，以及3）增强了她在物理科学家临床研究和临床试验设计方面的技能和知识。 Erdbrügger博士致力于将其研究计划扩展到描述性研究之外，并使用新开发的技能，知识，产品合作和数据形式正在进行的研究，以机械定义MPS在高血压和内皮功能障碍中的积极/功能作用。该提案的结果将用于准备R01申请，该申请将在K23奖的后期提交。职业发展计划包括教学课程工作，以使Erdbrügger博士对流式细胞仪的先进和全面了解，以及以患者为导向的研究和动物研究的进行。 机构环境：弗吉尼亚大学为拟议的研究提供了一个绝佳的环境。从肾脏诊所（基本/耐药性高血压），内分泌学诊所（用于原发性高氧化醛溶剂（PHA）），对干预放射学的大型转诊基础（用于肾脏血管性高血压（用于肾脏性高血压）（包括纤维肌肉发育不良（FMD）的良好研究者（包括良好的研究者）（包括肾脏肌肉发育不良的术语），该研究的良好研究者（包括肾脏肌肉症），可培训的良好研究者（包括肾脏肌肉症），该研究的良好研究（FMD）研究（均为良好的研究员） Le和Robert Carey，她的主要院长），《生物统计学》（Jennie MA博士，导师）和先进的流式细胞仪（Joanne Lannigan），共同为成功执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：这项受过指导的以患者为导向的研究职业发展奖（K23）的申请旨在在早期或前临床器官损害特定形式的高血压（HTN）中确定循环和尿型微粒（MPS）的诊断作用。 MP是从各种细胞类型的小膜片段的异质种群，并带有其母细胞的特定标记。作为内皮功能障碍和血管损伤的潜在新生物标志物，他们引起了极大的关注。但是，这些先前对MP的研究主要是在体外进行的。拟议的研究将是第一个使用一种新颖，更灵敏的成像流式细胞术方法来研究内皮起源的MP，Erdbrügger博士和Joanne Lannigan开发了用于检测MPS的MPS。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）的小鼠中，大多数内皮衍生的MPS在2周内诱导了HTN，并且在目的地4周后持续HTN后减少。相比之下，只有白细胞衍生的MP会随着时间的推移而增加，并且与HTN的严重程度最好。在AIM 1中，我们将测试以下假设：MPS的特定子集以自发性高血压大鼠（SHR）（SHR）和HTN发育发育前后的中风（SHRSP）释放，并且MPS亚型的水平随着HTN和HTN的严重程度而变化。此外，我们将在这些大鼠的尿液中检测到尿液中的足细胞衍生的MP，作为肾脏高血压损害的早期标志。 Erdbrügger博士还发现，与使用一氧化氮合酶抑制剂L-NAME相比，ANG II引起的HTN诱导的HTN中不同类型的内皮衍生的MP显着升高，这表明内皮损伤的机制不同。在AIM 2中，我们将检验以下假设：由于必不可少的HTN，纤维肌肉发育不良和PHA，来自HTN患者的MPS的亚型将是特定于诊断性的，并且在疾病特异性干预后将降低。我们进一步假设，在FMD中干预血管成形术或手术去除PHA中的肾上腺腺瘤后，MPS的水平将降低。在这些高血压患者中，还将检测到足细胞衍生的MP作为肾脏损伤的早期标记。从该项目中获得的知识将实时揭示对高血压的血管反应。我们的工作将是定义HTN特定形式的血管损害的占地面积或后果的第一步，以便将未来的投资用于机械地描述血管损伤的确切性质。