Adrenomedullin, Chemokine Receptors, and Receptor Activity Modifying Proteins in Lymphangiogenesis Public Deposited

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  • March 19, 2019
Creator
  • Klein, Klara
    • Affiliation: School of Medicine, Department of Cell Biology and Physiology
Abstract
  • Over the past decade, we have begun to appreciate that the lymphatic vascular system does more than simply return plasma back into the circulatory system and, in fact, contributes to a wide variety of normal and disease states. For this reason, much research has been devoted to understanding how lymphatic vessels form and function, with a particular interest in which molecules contribute to lymphatic vessel growth and maintenance. Here, we have focused on a potent lymphangiogenic factor, adrenomedullin, and its known roles in lymphangiogenesis, lymphatic function, and lymphatic disease. In the course of our studies, we have discovered that the decoy receptor CXCR7 is required as a molecular rheostat for controlling the concentration of AM ligand during cardiac and lymphatic vascular development. Loss of mammalian CXCR7 results in postnatal lethality due to aberrant cardiac development and myocyte hyperplasia. In Part I, we provide the molecular underpinning for this proliferative phenotype by demonstrating that the dosage and signaling of adrenomedullin is tightly controlled by CXCR7. To this end, Cxcr7-/- mice exhibit gain-of-function cardiac and lymphatic vascular phenotypes which can be reversed upon genetic depletion of adrenomedullin ligand. In addition to identifying a biological ligand accountable for the phenotypes of Cxcr7-/- mice, these results reveal a previously underappreciated role for decoy receptors as molecular rheostats in controlling the timing and extent of GPCR-mediated cardiovascular development. In Part II, we investigated whether CXCR7 and related chemokine receptors (CKRs), CXCR4 and CCR5, form protein-protein interactions with one component of the AM signaling system, Receptor Activity Modifying Proteins (RAMPs). BRET studies, confocal microscopy, and fluorogen-activating protein assays indicate CKRs associate with RAMP2 and RAMP3 in vitro, suggesting that a broader group of GPCRs interact with RAMPs than previously thought. Future studies will allow us to characterize the breadth of RAMP interactions, facilitating a shift in the focus of RAMP research to the design of functional assays that help determine whether a given GPCR-RAMP association affects biological activity. A thorough understanding of RAMP effects on biology has the potential to have significant clinical impact, as targeting of the RAMP-GPCR interface could yield specific, high affinity drugs.
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  • In Copyright
Advisor
  • Bautch, Victoria
  • Faber, James
  • Tarrant, Teresa
  • Caron, Klara
  • Dudley, Andrew
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2015
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  • Chapel Hill, NC
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