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Hypertension & Renal Center of Excellence
1430 Tulane Avenue
New Orleans, LA 70112
Phone: (504) 988-3703
Fax: (504) 988-2675

 

COBRE: PAST JUNIOR FACULTY INVESTIGATORS


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Because hypertension and associated kidney & cardiovascular diseases are highly prevalent in Louisiana, Tulane Health Sciences Center established a Hypertension & Renal Center of Excellence (THRCE), which has developed rapidly as a consequence of the support received by the NIH COBRE award.  In 2002, the center was awarded the Phase I grant from the National Institutes of Health in order to establish a Center of Biomedical Research Excellence (COBRE) in Hypertension and Renal Biology.  It was awarded the COBRE phase II award in 2007 and in 2012, it was awarded the COBRE Phase III award to support and maintain the various research core facilities that were established during COBRE phases I and II.  Since 2002 till 2012, COBRE Phases I and II provided support for 16 junior faculty members, of which 7 received NIH research funding, 19 postdoctoral fellows, 12 graduate students, and 29 medical students. The following are research projects that were supported by COBRE.

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Past Projects & Investigators

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Tubular Renin-Angiotensin System in Hypertension

Junior Faculty Investigator: Hiroyuki Kobori, M.D., Ph.D.
Dr Kobori received research training as a postdoctoral research fellow in developmental nephrology. In order to become clinically qualified, he then completed a pediatric residency and a pediatric nephrology fellowship. While his research during his fellowship was concentrated on the role of bradykinin B2 receptor in renal development, his project represented an independent line of investigation that was focused on the role of the renin-angiotensin system in distal nephron development.

Research:
The concomitant increases in renal angiotensinogen (AGT) protein and AGT mRNA that occurs during chronic angiotensin (ANG) II infusions provides a firm foundation for the hypothesis that enhanced intrarenal AGT production contributes to the increased intrarenal ANG II levels and the altered renal function that leads to the progressive development of hypertension in ANG II-dependent hypertensive rats. However, the mechanisms responsible for the ability of moderate increases in circulating ANG II to cause progressive increases in arterial pressure remain incompletely understood. The central hypothesis of this project is that ANG II-dependent hypertension is characterized by augmented proximal tubular AGT secretion leading to increased distal nephron spillover of AGT coupled with stimulation of distal tubular renin formation leading to increased distal formation of ANG II and enhanced ANG II-mediated sodium reabsorption. Furthermore, the distal nephron spillover of AGT is reflected by increased urinary AGT excretion rates, which can be used as an index of intrarenal ANG II activity. Our central hypothesis will be evaluated by pursuing the following specific aims:

  1. To establish that urinary AGT excretion rate is a specific index of intrarenal AGT and ANG II activity and not just a consequence of hypertension or proteinuria.
  2. To separate the effects of increased ANG II type 1 receptor stimulation from elevated arterial pressure in mediating the augmented intrarenal AGT mRNA, protein, and urinary excretion rates.
  3. To characterize the distal tubular renin protein and mRNA expression profile in rat kidneys.
  4. To determine the effects of chronic ANG II infusions on distal nephron renin protein and mRNA levels.

It is expected that the results of these experiments will establish that there is a very close relationship between urinary AGT and intrarenal AGT and ANG II production, and that there is both augmented AGT and distal nephron renin expression and activity leading to an increased ANG II-mediated sodium reabsorption in distal nephron segments of ANG II-infused hypertensive rats. It is further projected that urinary AGT excretion rates may provide a useful test in human hypertensive subjects to identify ANG II-dependent hypertension.

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Angiotensin Receptors in Renal Microvascular Physiology

Junior Faculty Investigator: Lisa Harrison-Bernard, Ph.D.
Dr. Harrison-Bernard had received extensive training in microcirculation as well as molecular biology of the renal renin-angiotensin system when she began her studies. She used, in her studies, transgenic mice and had developed an independent line of investigation using mice with deletion of the genes for the angiotensin II type (AT1) receptor subtypes.

Angiotensin (Ang) II has powerful effects on the kidney, which are mediated primarily by the angiotensin type 1 (AT1) receptor. There are two unique AT1 receptor subtypes in rodents, AT1A and AT1B, which cannot be distinguished using pharmacological antagonists. The human AT1 receptor amino acid sequence more closely resembles the rat AT1A than AT1B receptor. Thus, we need to know what role, if any, the AT1B receptor contributes to the overall function of the AT1 receptor paradigm. If the effects of AngII are proportional to the number of receptor sites at the cell surface, the subtype-specific mode of regulation ensures differentiated effects in different target cells via two very similar receptor subtypes using a single ligand. Thus, there is a greater need to explore AT1A receptor function in the absence of AT1B receptors and of the AT1B receptor function in the absence of AT1A receptors particularly as related to AngII regulated microvascular function in the kidney.

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Angiotensin in Distal Nephron Ontogeny

Junior Faculty Investigator: Ihor V. Yosypiv, M.D.
Dr. Igor received research training as a postdoctoral research fellow in developmental nephrology. In order to become clinically qualified, he then completed a pediatric residency and a pediatric nephrology fellowship. While his research during his fellowship was concentrated on the role of bradykinin B2 receptor in renal development, his project represented an independent line of investigation that was focused on the role of the renin-angiotensin system in distal nephron development.

Research:
Human renal malformations are the major cause of renal failure and hypertension during early childhood, accounting for approximately 30-40% of end-stage renal disease in children under 4 years of age. Recent studies indicate that inactivation of the genes encoding components of the renin-angiotensin system (RAS) in mice cause abnormalities in the development of renal pelvis and calyces. Angiotensinogen (Ao), angiotensin-converting enzyme (ACE), and AngII AT1 receptor-deficient mice demonstrate progressive widening of the calyx and atrophy of the papilla. Collectively, multiple lines of evidence suggest that intact RAS is required for nephrogenesis and the development of renal papilla. Our preliminary results indicate that Ao, AT1 and AT2 receptor proteins and ACE activity are all present in murine uretic bud (UB) cells of fetal origin and in inner medullary collecting duct (IMCD3) cells in culture, indicating that the two cell types that are commonly utilized to examine renal epithelial morphogenesis express major components of the RAS.
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Heme-Heme Oxygenase-Carbon Monoxide System in Salt-Induced Hypertension

Junior Faculty Investigator: Fruzsina Johnson, M.D.
Dr. Johnson was an outstanding junior scientist who was completing a postdoctoral fellowship when she began her studies. Dr. Johnson has been involved in research studies since 1996 having completed the equivalent of a Ph.D. with first author papers in peer reviewed journals. She has also won several prestigious awards from several societies including the Council for High Blood Pressure of the American Heart Association. She represented the emerging generation of leaders in hypertension research.

Research:
Vascular endothelial and smooth muscle cells express heme oxygenase, that catalyzes the conversion of heme to biliverdin and carbon monoxide. The two major isoforms of heme oxygenase are the inducible heme oxygenase-1 and the constitutive heme oxygenase-2. Pathological conditions, including hypertension, can increase heme oxygenase-1gene expression. While carbon monoxide relaxes vascular smooth muscle, it also inhibits nitric oxide (NO) synthase (NOS) by competing with L-arginine. In isolated skeletal muscle arterioles, heme-derived carbon monoxide causes endothelium-dependent vasoconstriction that is converted to vasodilatation in the presence of an inhibitor of NOS.

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The Role of Genetic Polymorphisms in the Epoxygenase Pathway in Hypertension

Junior Faculty Investigator: Albert Dreisbach, M.D.
When Dr. Dreisbach began his studies, he was a new faculty member in the Division of Nephrology who was interested in clinical investigations relevant to hypertension and renal diseases. He had extensive training doing fellowships in both Nephrology/Hypertension and Clinical Pharmacology. He also worked in the pharmaceutical industry for a time, giving him broad experience. This combination of experiences and disciplines is virtually unique and yet extremely important. His promise as an investigator is illustrated by a recent Faculty Development Award from the Pharmacueitical Research and Manufactures of America Foundation. Thus, he represetns physician-scientists performing clinical research, a group that has been reported to be dwindling an dhas been targeted special support.

Research:
Vasoactive arachidonic acid metabolites of the epoxygenase pathway, the epoxides, have been implicated in animal and human studies as factors which contribute to hypertension. The epoxide 11-12 epieicosatrienoic acid, the putative endothelium derived hyperpolarizing factor (EDHF) is formed by cytochrome P450 CYP2C9. CYP2C isozymes and epoxide hydrolase have been shown to catalyze the formation of the arachadonic acid metabolites, the epoxyeicosatrienoic acids (EETs) which are vasodilator epoxides presumed to include the endothelim derived hyperpolarizing factor (EDHF). CYP2C9 exhibits a high prevalence of genetic polymorphisms and phenotypes (up to 20% of certain populations), which may lead to altered levels of expoxides and reduced formation of EDHF in hypertensive patients. The altered vasoactive epoxide profile produced by CYP2C9, CYP2C8, and the epoxide hydrolase genetic polymorphisms may play a mechanistic role in hypertension.

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Beneficial Effects of Physical Activity on Blood Pressure among African-American Females

Junior Faculty Investigator: Paul Muntner, Ph.D.
Dr. Muntner was just appointed junior faculty member in the Department of Epidemiology when he began his studies and represented the investigators involved in population sciences and prevention research. His project represented efforts related to the investigation of various etiologic factors in the pathway leading to hypertension control but was an independent line of investigation distinct from that of his mentors.

Research:
A recent meta-analysis demonstrated that physical activity reduces blood pressure in hypertensive patients. However, there is a paucity of data regarding the beneficial effects of physical activity on lowering blood pressure in female African-American hypertensive subjects. The magnitude of blood pressure reduction attributable to aerobic exercise may differ by body mass. We propose to conduct a randomized clinical trial of a physical activity program among African-American females. The age-adjusted incidence and prevalence of hypertension is substantially higher among African-American females compared to White sub-groups. The proposed clinical trial will provide much needed evidence regarding the benefits of physical activity among African-American females. Evidence of a blood pressure (BP) lowering effect from aerobic exercise in the proposed clinical trails may assist in the promotion of physical activity among African-American females
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Heme Oxygenase in Angiotensin II Hypertension

Junior Faculty Investigator: Fady T. Botros, Ph.D.
Dr. Botros received his Ph.D. in the Department of Pharmacology at New York Medical College in 2004.  He completed his postdoctoral fellowship with us in the Department of Physiology and was appointed as Instructor in January 2007.  His research interests included cardiovascular and renal physiology with emphasis on the role of the heme-heme oxygenase (HO) system in normal regulation of vascular function and how dysfunction of this system may contribute to the development of hypertension. Dr. Botros was appointed a position at Lilly Pharmaceuticals.

Research:
Hypertension affects about 33 % of the population; if not controlled, it may cause end organ damage including renal failure. The angiotensin II-infused rat is a model for angiotensin II-dependent hypertension, in these rats both kidneys are exposed to elevated levels of angiotensin II and elevated perfusion pressure. Previous studies have shown that heme oxygenase (HO), an enzyme that catalyzes the conversion of heme to biliverdin, free iron and carbon monoxide (CO), is upregulated in kidneys from angiotensin II-infused rats indicating a possible protective role of heme oxygenase in angiotensin II-mediated hypertension. We hypothesize that heme oxygenase is upregulated in kidneys of angiotensin II-dependent hypertensive rats, and that HO-derived metabolites (CO and/or bilirubin) regulate renal hemodynamics by counteracting the effects of elevated angiotensin II levels and dilating the renal afferent and efferent arterioles, thus improving renal function. The aims of this study are: 1) To determine the effect of chronic angiotensin II infusion on renal arteriolar and tubular HO expression using immunohistochemical and western blot analyses. 2) To determine the effect of HO induction or inhibition on afferent and efferent arteriolar vasoactivity and responsiveness to angiotensin II, and on afferent arteriolar autoregulatory responses in normotensive and angiotensin II-hypertensive rats. Afferent and efferent arteriolar responses will be evaluated using the blood-perfused juxtamedullary nephron preparation. 3) To determine the effect of acute HO inhibition on renal hemodynamics, autoregulation, and pressure-natriuresis in angiotensin II-infused rats, using in vivo renal clearance studies.

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Mechanism of Resistance Artery Structural Remodeling in Hypertension

Junior Faculty Investigator: Khalid Matrougui, Ph.D.
Dr. Khalid Matrougui graduated from the University of Paris VI, France, earning his MS in 1995, and his PhD in 1998. His post-doctorial trainings were at the Aarhus University, Denmark, the University Paris VII, France, and the University of Alabama at Birmingham, USA. Before joining Tulane, Dr. Matrougui was Faculty Instructor at UAB's department of Biophysics & Physiology and faculty member at Louisiana State University Health Science Center. Dr. Matrougui joined Tulane School of Medicine in 2007, bringing with his appointment a new dimensions of expertise related to the growing efforts in Vascular Biology and Pathophysiology of Hypertension.

With the funding, resources, and mentorship provided through COBRE, Dr. Matrougui successfully secured an NIH RO1 award and therefore has graduated as a junior faculty investigator but will continue to interact with the COBRE group. He is currently an Associate Professor at the Department of Physiology at Eastern Virginia Medical School.

Research:
Hypertension, the most important risk factor for cardiovascular disease, is at epidemic levels in the UNITED STATES being responsible for increased prevalence of vascular complications, and morbidity and mortality. Many studies have shown mophological changes in resistance arteries (RA) from hypertensive patients and animal models; however, in vivo signaling pathways contributing to vascular structural remodeling in hypertension are poorly understood. Preliminary data show increased collagen type 1 content, artery stiffness and eutrophic structural remodeling induction of RA from angiotensin II (ANG II)-dependent hypertensive mice. Those RA morphological changes are associated with increased oxidative stress, inhibitory IkappaB proteins (IKB) phosphorylation, p50/p65 Nuclear Factor kappa B (NFkB) phosphorylation and translocation to the nucleus, avß3-integrin shedding, and TGFß1 expression. Based on these findings, Dr. Matrougui hypothesizes that elevated oxidative stress activates NFKB pathway leading to increase of avß3-integrin shedding and/or TGFß1 expression and bio-activity, which induces abnormal accumulation of collagen type 1 responsible for structural wall remodeling and increased stiffness of RA from ANG II-dependent hypertensive mice. The goals of this project are: 1) To demonstrate that increased collagen type 1 content, stiffness, and eutrophic remodeling induction are dictated by enhanced oxidative stress-dependent NFKB pathway activation of RA from ANG II-dependent hypertensive mice. In this aim we will determine that oxidative stress is upstream signaling that activates NFkB pathway responsible for morphological changes of RA from ANG II-dependent hypertensive mice. 2) To delineate the role of enhanced avß3-integrin shedding and TGFß1 expression on increased collagen type 1 content and stiffness, and eutrophic remodeling induction of RA from ANG II-dependent hypertensive mice. In this aim we will establish the role of avß3-integrin and TGFß1, down stream signaling to oxidative stress and NFkB, regulating collagen type 1 turnover, structural remodeling and stiffness of resistance arteries from ANG II-dependent hypertensive mice.



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Transcriptional Control of Ureteric Bud Growth and Branching


Junior Faculty Investigator: Zubaida Saifudeen, Ph.D.
Dr. Saifudeen joined the Section of Pediatric Nephrology at Tulane University School of Medicine in July 1999 as a Postdoctoral fellow. After completing a NRSA fellowship (2002-2005) in Dr. Samir El-Dahr's lab, Zubaida stayed on as Research Assistant Professor at Tulane Pediatrics. Early in her post-doctoral fellowship, Zubaida discovered that the bradykinin B2-receptor (B2R), a G-protein coupled seven transmembrane receptor, is a p53-target gene (JBC, 2000), a novel finding which had many important scientific implications.

Dr. Saifudeen has recently been awarded a COBRE Phase III Pilot Project grant and is working on her grant application in order to secure extramural funding. She is currently an Asociate Professor in the Department Pediatrics, Section of Nephrology, Tulane University School of Medicine.

Research:
The goal of Dr. Saifudeen's project was to understand the role of p53 protein in early kidney development, as aberrations during the early stages of development can lead to congenital defects. Dr. Saifudeen found that loss of p53 in mice embryos causes kidney structure and growth abnormalities (kidney/ureter duplication, obstruction of ureter). Infants born with duplex kidneys may suffer from unilateral or bilateral vesicoureteral reflux, hydronephrosis, and cystic-dysplasia.

A subset of p53-null/deficient mice exhibit profound defects in early renal development including duplex ureters/kidneys, hypoplasia and hydronephrosis.  The etiology of these abnormalities is currently unknown.  The objective of her COBRE project was to elucidate the role of p53 in early events of renal development with specific emphasis on UB outgrowth and patterning.  The overall hypothesis was that p53 expression in the metanephric anlagen was required to restrict UB induction to one specific site along the nephric duct.  In Specific Aim 1, the nephric cell lineage in which p53 expression was required to restrict UB induction to a specific site on the nephric duct was determined by A) in situ hybridization, and B) Conditional deletion of the p53 ORF from either the UB or the MM using cre-lox transgenic mice. In Specific Aim 2, she proposed to investigate the mechanisms by which p53 controls UB growth and branching.  Identifying how p53 works in early kidney development was an important step to formulating new therapies against congenital kidney diseases.



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Citrate transport in the proximal tubule


Junior Faculty Investigator: Kathleen S. Hering-Smith, Ph.D.
Dr. Hering-Smith has extensive experience in studies of sodium transport and acid-base transport including that of citrate; these studies have primarily utilized isolated perfused tubules, cell culture, and a variety of cell and molecular techniques.  Her career as an independent investigator began after she received her PhD from Tulane University in 2004.

With the funding, resources, and mentorship provided through COBRE, Dr. Hering-Smith successfully secured an NIH RO1 award and therefore has graduated as a junior faculty investigator but will continue to interact with the COBRE group. Shee is currently an Asistant Professor in the Department of Medicine

Research:
Urinary citrate is one of the most important inhibitors of calcium nephrolithiasis Various studies estimate that 19-63% of individuals with calcium containing kidney stones have hypocitraturia as a contributing cause.  Understanding the mechanisms of the regulation of citrate transport will hopefully lead to improved diagnosis of causes of hypocitraturia. Urinary citrate is an important inhibitor of calcium nephrolithiasis and is primarily determined by fractional reabsorption in the proximal tubule. The dicarboxylate transporter (NaDC1) is presumably the main mechanism of apical uptake of filtered citrate along the nephron. The most important physiologic regulator of urinary citrate excretion is acid-base status. Also urinary citrate increases as urinary calcium increases.

The proposed studies will address the acute regulation of citrate transport by calcium, and chronic regulation of citrate transport by acid-base perturbations and hypokalemia. Using a newly characterized in vitro model of citrate transport, OK cells studied under particular conditions, citrate and dicarboxylate uptake are sensitive to extracellular calcium. These studies indicate that the OK cell citrate transport system is likely a novel citrate transporter.  Recently another cell line of dicarboxylate transport was developed.  Human retinal pigmented epithelial cells stably transfected with human NaDC1 (CUBS cells) are responsive to acid-base conditions in vitro and will therefore represent a powerful new model. Two hypotheses will be examined: 1. Calcium acutely inhibits a novel citrate transport process in mammalian proximal tubule cells.  2. Chronic regulation of proximal tubule transport of citrate is accomplished by redundant mechanisms including changes in NaDC1 protein production and insertion of pre-existing NaDC1 protein into the apical membrane from sub-apical vesicles.  The specific aims are:  1.  To delineate the calcium sensitive citrate transport process by: demonstrating that the calcium sensitive citrate transport process is a novel transporter, not NaDC1, and determining the cellular mechanisms whereby extracellular calcium alters this citrate transport process. 2.  To delineate the mechanisms of chronic regulation of citrate transport by acid-base perturbations and hypokalemia.  To achieve this aim three modes of regulation will be examined: transcriptional (or mRNA stability) regulation, regulation at the protein level, and regulation by trafficking of NaDC1 into and out of the apical membrane from sub-apical vesicles under conditions of metabolic acidosis and hypokalemia.



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Distal Nephron Renin & Prorenin Receptor in Angiotensin II-dependant Hypertension


Junior Faculty Investigator: Minolfa C. Prieto, M.D., Ph.D.
Minolfa C. Prieto-Carrasquero, MD, PhD joined the Physiology Department of Tulane School of Medicine on July 1st, 2007, as Assistant Professor. Before that, she was recently a faculty at the University of Arizona Dr. Prieto-Carrasquero obtained her MD degree from the University of Zulia, Faculty of Medicine, at Maracaibo in Venezuela in 1985, and her PhD degree in Renal Physiology, dissertation title, “Distal Nephron Renin Regulation in Angiotensin II-dependant Hypertension,” from the Tulane University Health Sciences Center in 2004.

Dr. Prieto has recently been awarded a COBRE Phase III Pilot Project grant and is working on her grant application in order to secure extramural funding. She is currently an Asociate Professor in the Department of Physiology.

Research:
Long-term consequences of high blood pressure including stroke, cardiorenal disease, and end-organ damage are, at least in part, due to a systemic and intrarenal activation of the renin angiotensin system. In contrast to the inhibitory effect that Angiotensin II (Ang II) exerts on renin synthesized by juxtaglomerular cells, renin produced in distal nephron segments is stimulated in Ang II-dependent hypertension. The recent cloned prorenin/renin receptor -(P)RR- expressed by the mesangial cells and the epithelial cells of the distal nephron, may play a role in the activation of intracellular signaling pathways and in the non-proteolytic activation of prorenin, thus leading to local tissue injury and enhanced generation of angiotensin peptides. Interaction of renin and (P)RR at the distal nephron segments may represent a new paradigm to explain the increased intrarenal generation of angiotensin peptides and may also help to explain the activation of local signaling pathways contributing to renal injury and hypertension. However, the mechanisms involved in the regulation of distal nephron renin, neither the contribution of its interaction with the (P)RR to the development and progression of the Ang II-dependent hypertension have been elucidated. This study will investigate the mechanisms responsible for the regulation of renin in the distal nephron segments mediated by the chronic Ang II infusions and the implications of the interaction between renin and (P)RR during changes of dietary salt in Ang II-dependent hypertension by targeting the following specific aims: 1) To determine if chronically increased intrarenal Ang II content enhances renin production in the distal nephron directly by activation of Ang II type 1 receptor or indirectly by stimulation of sodium reabsorption via activation of amiloride-sensitive epithelial sodium channels and/or stimulation of aldosterone/specific mineralocorticoid receptors. 2)To determine the effects of changes in dietary salt on renin and the (P)RR in distal nephron segments during Ang II-dependent hypertension; and 3)To determine whether chronic administration of the specific renin inhibitor Aliskiren, can attenuate the salt sensitivity hypertension and related intrarenal oxidative stress and kidney injury in chronic Ang II-infused rats by inhibition of renin and (P)RR in distal nephron segments.



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Macronutrient Composition of Diet and Risk Factors for Cardiovascular Disease


Junior Faculty Investigator: Lydia A. Bazzano, M.D., Ph.D., M.PH.
Dr. Bazzano received both her MD and Ph.D. from Tulane University , earning her Ph.D from the Department of Epidemiology in 2000 and MD in 2002.  She completed her Medical Internship and Residency at Harvard Medical School , and in 2005, was appointed as Assistant Professor of Epidemiology in  the Tulane University School of Public Health and Tropical Medicine.  Her proposed study addresses important clinical and public health issues, which will contribute to our knowledge regarding the efficacy of low-carbohydrate diets on traditional and novel cardiovascular disease risk factors.

With the funding, resources, and mentorship provided through COBRE, Dr. Bazzano successfully secured an NIH RO1 award and has since graduated as a junior faculty iinvestigator. She is currently an Associate Professor in the Department of Epidemiology

Research:
Cardiovascular diseases (CVD) remain the leading cause of death globally as well as here in the United States . Manipulations of the macronutrient (protein, carbohydrate and fat) contents of diet have been used extensively for weight loss and weight control in the past several decades. Low carbohydrate diets, in particular, have gained popularity for weight loss. However, few studies have examined the effects of a diet low in carbohydrates on traditional and novel cardiovascular risk factors in the long term, particularly in contrast to the current dietary recommendations for decreased fat intake to reduce risk of CVD. In this proposal, we plan to conduct a 12-month, parallel-arm, randomized controlled trial of a diet low in carbohydrates versus the currently recommended diet low in fat diet to reduce CVD risk factors among obese adults. The objective of this trial is to examine the long-term effects of a diet low in carbohydrates, as compared to one low in fat, on CVD risk factors, including blood pressure (BP), body weight and composition, serum lipids, plasma glucose, insulin, adipocytokines (adiponectin, leptin, resistin), and C-reactive protein (CRP) among obese adults. In order to accomplish these objectives we will randomize 130 eligible participants (n=65 in each group) to consume either a diet low in carbohydrates (<40 g/d) or a diet low in fat (<7% saturated fat, <35% total fat). Neither of the diets will be energy-restricted. Participants will meet with a dietitian for one-on-one counseling session weekly for the first 4 weeks, then bi-weekly in small group sessions for the next 5 months, and monthly in larger group sessions for the final 6 months of the intervention. Data on both traditional and novel CVD risk factors will be collected at baseline, 3, 6, and 12 months. We hypothesize that a diet low in carbohydrates as compared to a diet low in fat will lower systolic and diastolic BP, body weight, total percent body fat, waist circumference, serum levels of triglycerides, and plasma levels of insulin, glucose, leptin, resistin, and CRP, and increase serum levels of HDL-cholesterol and adiponectin. Because CVD is the most common cause of death here in the U.S. and world-wide, this study has important public health implications. It will provide new information on the potential long-term effects of diets low in carbohydrates on both the traditional risk factors for CVD as well as novel risk factors and inflammatory factors.  The results from this study will help to determine if a diet low in carbohydrates as compared to the currently recommended low fat diet can decrease the risk of CVD among obese adults. In addition, this trial will provide the junior investigator, Dr. Bazzano, an opportunity to acquire research skills and experience necessary to launch a successful, sustainable, and independent research career in the investigation and dietary and lifestyle approaches to reduce risk factors for hypertension and CVD.



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Endothelial Dysfunction, Adipocytokins, Inflammation & Chronic Kidney Disease


Junior Faculty Investigator: Jing Chen, M.D., M.Sc.
Dr. Chen received her MD at Jiangxi Medical College , PR China, in 1984 and MSc in Biotechnology from Johns Hopkins University   in 1995. She was appointed Assistant Professor in the department of Medicine, section of Nephrology in 2003. Her research interest is primarily related to the role of endiothelial dysfunction in contributing to chronic kidney disease and related cardiovascular disease.

Research:
Chronic kidney disease (CKD) has become an important public health challenge in the United States. CKD is a major risk factor for end-stage renal disease (ESRD), cardiovascular disease (CVD), and premature death. Understanding novel risk factors for CKD may provide effective approaches for early intervention in order to reduce the morbidity and mortality related to CKD. Endothelial dysfunction, adipocytokines and inflammation have been associated with ESRD and CVD in small clinical studies and animal experiements. However their role in the etiology of CKD has not been established.  The overall objectives of this proposed study are to examine the effects of endothelial dysfunction, adipocytokines, and inflammation on the risk of CKD.

The specific aims of the proposed study are:  (1) to examine the association between biomarkers of endothelial dysfunction (plasma levels of asymmetric dimethylarginine, endothelin-1, intercellular adhesion molecule-1, vascular cell adhesion molecule 1, E-selectin, L-arginine and NO2/NO3 (NOx), and urinary excretion of NO2/NO3 (NOx)) as well as endothelial function assessed by brachial artery reactivity using high-resolution ultrasound and risk of CKD; (2) to examine the association between adipocytokines (leptin, resistin, and adiponectin) and risk of CKD; (3) to examine the association between inflammation (C-reactive protein, interleukin-6, and tumor necrosis factor-a) and risk of CKD; and (4) to examine the correlation between biochemical markers of endothelial dysfunction and endothelial function assessed by brachial artery reactivity using high-resolution ultrasound.

This study has important clinical and public health implications. Understanding the nature of endothelial dysfunction, adipocytokines and inflammation in patients with CKD will provide insight into developing tailored intervention strategies including normalizing endothelial dysfunction, targeting adipocytokines and inflammation for the prevention and treatment of CKD and related CVD. In addition, the proposed study, if funded, will provide important preliminary data to conduct a prospective cohort study to examine the longitudinal association of endothelial dysfunction, adipocytokines and inflammation with the progression of CKD and related CVD.



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The Effect of Microvascular Patterning Alterations on Network Resistance in Spontaneously Hypertensive Rats


Junior Faculty Investigator: Walter Lee Murfee, Ph.D.
Dr. Murfee, also an adjunct assistant professor in the Department of Physiology at Tulane University, received his Ph.D. from the Department of Biomedical Engineering at the University of Virginia in the laboratory of Dr. Thomas Skalak and was a postdoctoral fellow in the Microcirculatory Laboratory with Dr. Geert Schmid-Schönbein in the Department of Bioengineering at the University of California – San Diego.

Research:
Hypertension is associated with an increase of microvascular resistance, in part, due to structural rarefactioncaused by the anatomical loss of microvessels. Given that elevated blood pressure is accompanied and in some cases preceded by this loss of microvessels, therapies aimed at reversing rarefaction represent candidate treatments for hypertension. However, assessing the potential for such therapies and requires a further mechanistic understanding of the relationship between network patterns and Microvascular resistance over the time course of the disease. Preliminary data suggests that microvascular rarefaction in the adult spontaneously hypertensive rat, a genetic model for hypertension, is more complex than just a loss of microvessels. Adult hypertensive microvascular networks are marked by arterial/venous anastomoses and altered perivascular cell expression of Neuron-Glia Antigen 2 (NG2), a chondroitin sulfate proteoglycan recently implicated in endothelial cell proliferation and migration.

Dr. Murfee hypothesize that Microvascular resistance is elevated in adult hypertensive due to altered microvascular network architectures associated with decreased perivascular expression of NG2. In order to test this hypothesis, the proposed studies will evaluate Microvascular network architecture and vessel-specific perivascular expression of NG2 over the time course of hypertension development; determine if hypertensive microvascular network architectures result from altered perivascular NG2 expression; and determine the effect of hypertensive microvascular network architectures on microvascular network resistance and vessel specific hemodynamics. The results from this study will establish new directions for investigating the influence of structural alterations at the network and cellular level on Microvascular resistance during hypertension and, thus, offer novel perspectives for designing hypertension therapies aimed at manipulating the microcirculation.


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