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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 Pilot Projects




2012-2013 Pilot Projects & Investigators

2012-2013 Pilot Project award recipients were Minolfa C. Prieto, M.D., Ph.D., Andrei V. Derbenev, Ph.D., and Zubaida Saifudeen, Ph.D.


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Prieto 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.

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ZS_IMG_0153 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.

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Derbenev 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.

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Tulane University, New Orleans, LA 70118 504-865-5000 website@tulane.edu