CANDIDATE: Dr. Erdbrgger 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. Erdbrgger 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. Erdbrgger 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. Erdbrgger 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. Erdbrgger and Joanne Lannigan developed to detect MPs. In exciting preliminary data, Dr. Erdbrgger 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. Erdbrgger 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.
: Hypertension (HTN) affects over 50 million Americans and is a major risk factor for a wide range of cardiovascular diseases. The proposed study will examine circulating and non-invasive urinary microparticles that are derived or shed from cells as markers for vascular and end organ damage. We will use an advanced technique that combines imaging flow cytometry with increased sensitivity to detect microparticles in-vivo in patients with essential hypertension and specific forms of hypertension but without any pre-existing cardiovascular disease, to determine the diagnosis-specific microparticle footprint. We will also characterize the specific types of microparticles in the spontaneously hypertensive rat (SHR) and the stroke prone SHR (SHRsp) before and after development of hypertension, and after high salt challenge, to correlate the types of microparticles with the severity of hypertension and end organ damage. This in-vivo animal model enables the analysis of microparticles over the course of disease development and progression to organ damage, as well as response to therapy. Our goal is to establish microparticles as early markers for end-organ damage from hypertension. Early detection and hence early intervention could potentially result in reduction of cardiovascular consequences caused by arterial hypertension.
