Urogenital System Development: The Acquisition of Coordinated Ureter Peristalsis

Summary

Principal Investigator: Doris A Herzlinger
Abstract: DESCRIPTION (provided by applicant): Coordinated contractions of the smooth muscle coat surrounding the kidney outflow tract (OT), including the renal calyces, pelvis and ureter, are essential for draining urine out of the kidney. Congenital defects that impair this peristaltic process are common, and the leading cause of renal failure in children. However, the signaling pathways that control the differentiation of the cell types mediating urinary tract peristalsis remain poorly understood. In the previous funding period we showed that Bone Morphogenetic Protein signaling during the early stages of development is essential for the formation of the OT smooth muscle coat. In this project we will study the differentiated cell types that coordinate contraction in this musculature. We recently discovered that the normal initiation and coordination of OT smooth muscle contraction is dependent on Hyperpolarizing Cation Channel (HCN) activity. In Aim 1, we will determine if HCN expressing OT cells exhibit the electrophysiological and structural properties required for triggering smooth muscle contraction using our recently developed high resolution video-microscopic and optical mapping protocols and electron-microscopic techniques. Moreover, we will determine if HCN channel activity is essential for the efficient flow of urine from the kidney to the bladder by analyzing OT structure, smooth muscle contractile and electrical activity in mice with targeted HCN gene deletions. We have also uncovered a role for the tyrosine kinase receptor C-kit in controlling OT contractile activity. In Aim 2 we will analyze OT architecture and smooth muscle function in mice with loss-of-function mutant C-Kit alleles using morphological and functional assays. Aim 3 is based on our preliminary data demonstrating that mice harboring a constitutively active C-kit allele develop fetal hydronephrosis. We will determine if this defect due to C-kit gain-of-function is caused by a structural occlusion of the OT tract or as we predict, a defect in coordinated peristalsis. Collectively, the results of proposed experiments identifying the cell types required for triggering coordinated OT peristalsis will open up a new area of investigation focused on the signaling pathways controlling the differentiation of these pacemaker cells. Ultimately, our studies will reveal drug targets for the modification of ureter peristalsis and may reveal unappreciated causes of hydronephrosis.
Funding Period: 1991-09-15 - 2016-07-31
more information: NIH RePORT

Top Publications

  1. ncbi Tailbud-derived mesenchyme promotes urinary tract segmentation via BMP4 signaling
    Andrea Brenner-Anantharam
    Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, NY 10021, USA
    Development 134:1967-75. 2007
  2. pmc Paraxial mesoderm contributes stromal cells to the developing kidney
    Richard Guillaume
    Weill Medical College of Cornell University, Department of Physiology and Biophysics, 1300 York Ave, New York, NY 10065, USA
    Dev Biol 329:169-75. 2009
  3. pmc The pelvis-kidney junction contains HCN3, a hyperpolarization-activated cation channel that triggers ureter peristalsis
    Romulo Hurtado
    Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, New York 10021, USA
    Kidney Int 77:500-8. 2010
  4. pmc Upper urinary tract pacemaker cells join the GLI club
    Doris Herzlinger
    Department of Physiology and Biophysics, Cornell University Medical College, New York, New York 10021 4805, USA
    J Clin Invest 121:836-8. 2011
  5. pmc A molecular signature of tissues with pacemaker activity in the heart and upper urinary tract involves coexpressed hyperpolarization-activated cation and T-type Ca2+ channels
    Romulo Hurtado
    1Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, NY 10021, USA
    FASEB J 28:730-9. 2014

Detail Information

Publications5

  1. ncbi Tailbud-derived mesenchyme promotes urinary tract segmentation via BMP4 signaling
    Andrea Brenner-Anantharam
    Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, NY 10021, USA
    Development 134:1967-75. 2007
    ....
  2. pmc Paraxial mesoderm contributes stromal cells to the developing kidney
    Richard Guillaume
    Weill Medical College of Cornell University, Department of Physiology and Biophysics, 1300 York Ave, New York, NY 10065, USA
    Dev Biol 329:169-75. 2009
    ..In addition, these fate mapping data indicate that renal development, like the development of all other tubular organs, is dependent on the integration of progenitors from different embryonic tissues into a single rudiment...
  3. pmc The pelvis-kidney junction contains HCN3, a hyperpolarization-activated cation channel that triggers ureter peristalsis
    Romulo Hurtado
    Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, New York 10021, USA
    Kidney Int 77:500-8. 2010
    ..This provides insight into the genetic causes of common inherited urinary tract disorders such as reflux and obstruction...
  4. pmc Upper urinary tract pacemaker cells join the GLI club
    Doris Herzlinger
    Department of Physiology and Biophysics, Cornell University Medical College, New York, New York 10021 4805, USA
    J Clin Invest 121:836-8. 2011
    ..These results link defective pacemaker cell differentiation with hydronephrosis and provide a cellular basis for one of the abnormal renal defects observed in humans with the GLI3-linked disease Pallister-Hall syndrome...
  5. pmc A molecular signature of tissues with pacemaker activity in the heart and upper urinary tract involves coexpressed hyperpolarization-activated cation and T-type Ca2+ channels
    Romulo Hurtado
    1Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, NY 10021, USA
    FASEB J 28:730-9. 2014
    ..Hurtado, R., Bub, G., Herzlinger, D. A molecular signature of tissues with pacemaker activity in the heart and upper urinary tract involves coexpressed hyperpolarization-activated cation and T-type Ca(2+) channels. ..

Research Grants30

  1. Genetic Analysis of Etv4/Etv5 Transcription Factors and Kidney Development
    FRANKLIN D COSTANTINI; Fiscal Year: 2013
    ..Lack of Adamts16 and/or 18 may cause reduced nephron number and hyper- tension. We test this by examining kidney development, nephron number and blood pressure in mutant mice. ..
  2. Calcium signaling in the cerebrovascular unit in health and disease
    Mark T Nelson; Fiscal Year: 2013
    ..The long-term objective is to understand blood flow in the brain in health and disease, and by doing so, to reveal exciting novel targets that can be exploited in the treatment of cerebrovascular disease. ..
  3. Strategies for Improved Shock Wave Lithotripsy
    JAMES ALEXANDER MCATEER; Fiscal Year: 2013
    ..and the session can be ended * Determine the mechanism by which cavitation within a vessel causes hemorrhage * Develop numerical models to understand the role of cavitation and non-cavitational mechanisms in causing tissue damage ..
  4. Distinct and Overlapping Pathways of Fibrosis and Emphysema in Cigarette Smokers
    Augustine M Choi; Fiscal Year: 2013
    ..4) Clinical Outcomes and Molecular Phenotypes in Smokers with Parenchymal Lung Disease Cores: 1) Administrative Core 2) Respiratory Computational Discovery Core 3) Clinical Biorepository Core 4) Murine Models and Molecular Analysis Core ..
  5. Autocoids in Hypertension: Pathogenesis and End Organ Damage
    Oscar A Carretero; Fiscal Year: 2013
    ..Te PPG provides integration of our efforts, collaboration, sharing of ideas and expertise, thus accelerating acquisition of knowledge on the causes of hypertension and EOD. (End of Abstract) ..
  6. Mechanisms/Treatments of Lower Urinary Tract Dysfunction After Spinal Cord Injury
    ANTHONY JOHN KANAI; Fiscal Year: 2013
    ..We are confident that our experience and unique approaches will lead to a very interactive and fruitful program. ..
  7. Ether Lipids, Elcosanoids, and Lung Cell Pathophysiology
    CHRISTINA CARROLL LESLIE; Fiscal Year: 2013
    ..By using multidisciplinary approaches, we will determine the structural identity of lipid mediators, the molecular mechanisms involved in their production and how they function to regulate lung responses. ..
  8. MITOCHONDRIAL ENCEPHALOMYOPATHIES AND MENTAL RETARDATION
    Salvatore DiMauro; Fiscal Year: 2013
    ....
  9. HORMONAL REGULATION OF BLOOD PRESSURE
    Michal Laniado Schwartzman; Fiscal Year: 2013
    ..ular tone, in the pathophysiology of hypertension and cardiovascular disease. ..
  10. Molecular Analyses and Interventions for Biodefense and Emerging Pathogens
    Olaf Schneewind; Fiscal Year: 2013
    ..Research and training at the GLRCE is governed by a mechanism involving ongoing review of scientific excellence and translational goals, inter-institutional advisory boards and external scientific advisory bodies. ..
  11. VASOMOTOR CONTROL OF DESCENDING VASA RECTA
    Thomas L Pallone; Fiscal Year: 2013
    ..We will test whether upregulation of HO-1 normalizes CaV conductance and membrane potential in Dahl/SS rats and examine the ability of intramedullary CaV blockade to augment perfusion of the medulla in those animals. ..
  12. Pulmonary Surface Liquid Homeostasis
    RICHARD CHARLES BOUCHER; Fiscal Year: 2013
    ..abstract_text> ..
  13. Regulatory Mechanisms In Intestinal Motility
    Kenton M Sanders; Fiscal Year: 2013
    ..The investigative team is highly synergistic and collaborative, and the PPG has a long track-record of productivity and novel discovery ..
  14. Mechanisms of Calcium-Calmodulin Mediated Ion Channel Gating
    Richard Aldrich; Fiscal Year: 2013
    ..Our studies will contribute to understanding the function of an important class of ion channel, and general principles of ion channel gating, calcium/calmodulin regulatory mechanisms, and allosteric control of protein function. ..
  15. Ureteric Bud Patterning
    Doris A Herzlinger; Fiscal Year: 2013
    ..The successful completion of these experiments will provide insight into the susceptibility of ureter morphogenesis to congenital defects. ..