T. H. R. C. E.

COBRE Pilot Projects

THRCE awarded $5.4 million grant to maintain the COBRE

In 2012, the Tulane Hypertension and Renal Center of Excellence was awarded a 5 year, $5.4 million grant in order to maintain the Center of Biomedical Research Excellence (COBRE) Phase III Translational Research in Hypertension and Renal Biology. The competitive award is administered by the National Institute of General Medical Sciences (NIGMS). The principal investigator (PI) of the award is Dr. L. Gabriel Navar who, along with Dr. L. Lee Hamm, will continue to direct the COBRE program.

Tulane University Hypertension and Renal Center of Excellence (THRCE) was first established in 2002 by the NIH as one of its Centers of Biomedical Research Excellence (COBRE Phase I) with a 5 year, $10.8 million grant.  Then in 2007, the center was successful in competing for the 5 year COBRE Phase II grant that awarded over $11 million to continue its research in the field of high blood pressure and its effect on the kidneys as well as the role of kidneys in the development of high blood pressure.  

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. In addition, the research infrastructure was markedly enhanced by the Molecular, Imaging, and Analytical Core with state-of-the-art facilities, and Transgenic Animal Core serving members of the Hypertension and Renal Center. The long-term goals of the COBRE Phase III Award are to provide an enriched environment to all investigators so that they can maintain nationally competitive status as well as to augment and strengthen the biomedical research capacity and infrastructure for Tulane investigators in hypertension, renal and cardiovascular disease. These goals will be achieved by:

1. Providing support for maintaining the COBRE research CORES developed during Phases I and II that are essential for continuing the center’s basic, clinical, and translational research. These Cores include the Administrative Core, Mouse Phenotyping Core, Molecular & Analytical Core, Transgenic & Animal Core and the Clinical and Translational Core
2. Enhancing the research infrastructure at Tulane Health Sciences Center in the multidisciplinary area of hypertension, renal and vascular biology thus maintaining and increasing national competitiveness for NIH and other federal grants by our faculty investigators.
3. Encouraging and facilitating collaborative interactions between basic science investigators and clinical translational scientists in hypertension and related areas at Tulane Health Sciences Center.
4. Sustaining a collaborative multidisciplinary research environment by providing support for research pilot projects and mentoring and training components. 

The overall outcome of COBRE Phase III will contribute to an increased understanding of the multiple interactions leading to the pathophysiological derangements that lead to hypertension and associated kidney and cardiovascular diseases. COBRE Phase III, like phases I & II, will continue to increase the number of competitive scientists in a disease specific area of extremely high biomedical relevance in this region. 

Each year, will provide three pilot projects $50,000 research support to selected scientists from the Medical School, the School of Public Health and Tropical Medicine, and the School of Science and Engineering. The pilot project awards will provide one year research opportunities for novel, innovative, highly competitive meritorious projects with high likelihood for garnering extramural research support. Projects that address important, novel and significant issues related to the broad area encompassed by hypertension, renal and cardiovascular research will be considered. Applications will be subjected to a rigorous internal and external review process to ensure that funds are provided only to highly meritorious pilot projects that are likely to lead to extramural research support and will stimulate multidisciplinary collaborative interactions. This year’s Pilot Project award recipients are Minolfa C. Prieto, M.D., Ph.D., Andrei V. Derbenev, Ph.D., and Zubaida Saifudeen, Ph.D.. The three pilot projects are as follows:

• Pilot Project 1:
  Functional Role of ProRenin Receptor in the Collecting Duct to the Development of Hypertensionlar.
  ~ PI: Minolfa C. Prieto, M.D., Ph.D., Mentor: Dr. L. G. Navar.
• Pilot Project 2:
  Role of p53 in Nephron Progenitor Cell Renewal and Differentiation.
  ~ PI: Zubaida Saifudeen, Ph.D., Mentor: Dr. Samir S. El-Dahr.
• Pilot Project 3:
  Regulation of inhibitory circuits in the RVLM by angiotensin II.
  ~ PI: Andrei V. Derbenev, Ph.D., Mentor: Dr. L. G. Navar.

Pilot Projects & Investigators

 
Minolfa C. Prieto, MD, PhD

Assistant Professor
Phone: (504) 988-2445
Room #: 4061

Email: mprieto@tulane.edu

MD: Universidad del Zulia, Venezuela, 1985
PhD: Tulane University, 2004
 

Functional Role of ProRenin Receptor in the Collecting Duct to the Development of Hypertensionlar.

Project Abstract:

There is a gap in understanding how in angiotensin (Ang)II-dependent hypertension there is augmented intrarenal and intratubular angiotensin (Ang)II formation, despite suppression of juxtaglomerular renin. As a result, AngII increases sodium reabsorption in the collecting duct, thus contributing to the development of hypertension. During AngII-dependent hypertension, there is augmented production and secretion of renin in the collecting ducts, in sharp contrast with juxtaglomerular renin. Increased renin enzymatic activity upon binding to the prorenin receptor (PRR) in the collecting duct, is associated to increase intrarenal AngII content and hypertension. However, the consequences of the interaction between renin and PRR in the collecting duct, and their role in the development of hypertension remain uncertain. Until this gap in knowledge is filled, understanding the paradigm of the local amplification mechanism that intrarenal AngII exerts on collecting duct renin, will be incomprehensible. The long-term goal is to define the contribution of PRR to the pathogenesis of hypertension. We hypothesize that in AngII-dependent hypertension, the activation of PRR in the collecting ducts by its natural agonists, renin and prorenin, enhances local renin activity, augments intrarenal/intratubular AngII levels, and leads to the development and progression of hypertension by increasing sodium reabsorption and blood pressure. We will specifically target the PRR gene in the collecting ducts using shRNA and Cre-loxp generated mouse model to address the following specific aims: 1) Characterization of the mouse model with deletion of the PRR in the collecting ducts; and 2) To test the hypothesis that PRR contributes to increase AngII levels and to the development of hypertension by enhancing activity of collecting duct-derived prorenin. It is expected to provide definitive evidence of the functional contribution of PRR to the enhancement of local renin activity in AngII hypertension and to obtain solid basis to support a national competitive funding application to elucidate the physiological inputs of PRR and their functional roles in pathological states.

Recent Publications: A PubMed listing of research publications for Minolfa Prieto, M.D., Ph.D.

 
Zubaida Saifudeen, PhD

Assistant Professor
Phone: (504) 988-5046
Room #: 5515

Email: zubisaif@tulane.edu

PhD: Tulane University, 1997

Role of p53 in Nephron Progenitor Cell Renewal and Differentiation.

Project Abstract:

Final nephron endowment is regulated by the availability of nephron progenitor cells (NPC) and their differentiation to nephrons. What determines final nephron number is not known. Reduced nephron mass at birth is strongly associated with development of adult-onset diseases such as hypertension, chronic renal failure and type 2 diabetes, thus significantly influencing long-term renal health. Additionally, decreased nephron endowment is a part of the congenital anomalies of the kidney and urinary tract syndrome, a major cause of morbidity in pediatric patients, contributing to 30-50% of end-stage renal disease and a significant cause of Chronic Kidney Disease in children and young adults. Elucidating mechanisms of self-renewal of the multipotent NPC population and its ability to differentiate to nascent nephrons will not only significantly advance our understanding of congenital determinants of nephron endowment, but also nephron regeneration programs for kidney repair. The overall goal of this proposal is to demonstrate that the tumor-suppressor p53 plays a key role in determination of the cell-fate of NPCs by promoting their renewal/survival and differentiation. Our preliminary data indicate a requirement for p53 for the maintenance of the progenitor cell pool, and their subsequent differentiation to nephron epithelia. Based on these data our overall hypothesis is that p53 is required for NPC self-renewal and differentiation. Accordingly, in Specific Aim 1 we will examine the effects of p53 deletion in specific cap mesenchyme (CM) sub-compartments on progenitor cell renewal and maintenance. Using lineage tracing we will follow the fate of NPCp53-/-. Since Fgf8 signaling from nascent nephrons has been shown to contribute to Cited1+ NPC survival, we will determine the contribution of the nephrogenesis defect to NPC renewal and survival after conditional p53 deletion from the induced Wnt4+ NPC population using Wnt4CreERT in Aim 2.

Approximately 40% of chronic kidney disease cases in children are caused by congenital anomalies of the kidney and urinary tract. This project will provide insight into the regulation of kidney progenitor cell renewal and differentiation. This will have significant impact on diseases that affect progenitor cell maintenance such as renal hypoplasia and Wilms tumor, and potential therapies that depend on stem cell regeneration.

Recent Publications: A PubMed listing of research publications for Zubaida Saifudeen, Ph.D.

 Andrei V. Derbenev, PhD

Assistant Professor
Phone: (504) 988-2053
Room #: 4012

Email: aderben@tulane.edu

PhD: Pavlov Institute of Physiology, Russian Academy of Science,
          Saint-Petersburg, Russia, 1999.

Regulation of inhibitory circuits in the RVLM by angiotensin II.

Project Abstract:

The central nervous system (CNS) is directly involved in the regulation of arterial blood pressure (ABP), largely through actions of the sympathetic nervous system (SNS). Renal sympathetic nerves have been identified as key contributors to the complex pathophysiology of hypertension both in human and experimental models (DiBona and Kopp, 1997; Krum et al., 2009; Schlaich et al., 2011). The “central neuron imbalance” hypothesis suggests that hypertension results from an imbalance between the tonic level of activity generated from the central sympathetic neuronal network and those cells that inhibit this excitatory drive. However, the underlying central mechanisms for the development of “neurogenic hypertension” remain poorly understood. This project will specifically investigate relationship between angiotensin II levels and suppressed tonic inhibition of kidney-related RVLM neurons via postsynaptic activation of angiotensin II type 1 receptor (AT1R). This approach also offers important clinical implications through direct evidence regarding the central regulation of cardiovascular function by GABAA receptor and, therefore, identifies novel therapeutic strategies in the treatment of hypertension.

Recent Publications: A PubMed listing of research publications for Andrei V. Derbenev, Ph.D.