Bharath Wootla

Publications (28) View all

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  Available from: Bharath Wootla

  Dataset: JCI57407sd

  Alexandre Loupy, Suresh Krishna Ramakrishnan, Bharath Wootla, Régine Chambrey, Renaud de la Faille, Soline Bourgeois, Patrick Bruneval, Chantal Mandet, Erik Ilso Christensen, Hélène Faure, Lydie Cheval, Kamel Laghmani, Corinne Collet, Dominique Eladari, Robert H Dodd, Martial Ruat, Pascal Houillier
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  Available from: Bharath Wootla

  Article: PTH-independent regulation of blood calcium concentration by the calcium-sensing receptor.

  Alexandre Loupy, Suresh Krishna Ramakrishnan, Bharath Wootla, Régine Chambrey, Renaud de la Faille, Soline Bourgeois, Patrick Bruneval, Chantal Mandet, Erik Ilso Christensen, Hélène Faure, Lydie Cheval, Kamel Laghmani, Corinne Collet, Dominique Eladari, Robert H Dodd, Martial Ruat, Pascal Houillier
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  ABSTRACT: Tight regulation of calcium levels is required for many critical biological functions. The Ca2+-sensing receptor (CaSR) expressed by parathyroid cells controls blood calcium concentration by regulating parathyroid hormone (PTH) secretion. However, CaSR is also expressed in other organs, such as the kidney, but the importance of extraparathyroid CaSR in calcium metabolism remains unknown. Here, we investigated the role of extraparathyroid CaSR using thyroparathyroidectomized, PTH-supplemented rats. Chronic inhibition of CaSR selectively increased renal tubular calcium absorption and blood calcium concentration independent of PTH secretion change and without altering intestinal calcium absorption. CaSR inhibition increased blood calcium concentration in animals pretreated with a bisphosphonate, indicating that the increase did not result from release of bone calcium. Kidney CaSR was expressed primarily in the thick ascending limb of the loop of Henle (TAL). As measured by in vitro microperfusion of cortical TAL, CaSR inhibitors increased calcium reabsorption and paracellular pathway permeability but did not change NaCl reabsorption. We conclude that CaSR is a direct determinant of blood calcium concentration, independent of PTH, and modulates renal tubular calcium transport in the TAL via the permeability of the paracellular pathway. These findings suggest that CaSR inhibitors may provide a new specific treatment for disorders related to impaired PTH secretion, such as primary hypoparathyroidism.
  The Journal of clinical investigation 08/2012; 122(9):3355-67. · 15.39 Impact Factor
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  Article: High-affinity binding of remyelinating natural autoantibodies to myelin-mimicking lipid bilayers revealed by nanohole surface plasmon resonance.

  Nathan J Wittenberg, Hyungsoon Im, Xiaohua Xu, Bharath Wootla, Jens Watzlawik, Arthur E Warrington, Moses Rodriguez, Sang-Hyun Oh
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  ABSTRACT: Multiple sclerosis is a progressive neurological disorder that results in the degradation of myelin sheaths that insulate axons in the central nervous system. Therefore promotion of myelin repair is a major thrust of multiple sclerosis treatment research. Two mouse monoclonal natural autoantibodies, O1 and O4, promote myelin repair in several mouse models of multiple sclerosis. Natural autoantibodies are generally polyreactive and predominantly of the IgM isotype. The prevailing paradigm is that because they are polyreactive, these antibodies bind antigens with low affinities. Despite their wide use in neuroscience and glial cell research, however, the affinities and kinetic constants of O1 and O4 antibodies have not been measured to date. In this work, we developed a membrane biosensing platform based on surface plasmon resonance in gold nanohole arrays with a series of surface modification techniques to form myelin-mimicking lipid bilayer membranes to measure both the association and dissociation rate constants for O1 and O4 antibodies binding to their myelin lipid antigens. The ratio of rate constants shows that O1 and O4 bind to galactocerebroside and sulfated galactocerebroside, respectively, with unusually small apparent dissociation constants (K(D) ≈ 0.9 nM) for natural autoantibodies. This is approximately one to 2 orders of magnitude lower than typically observed for the highest affinity natural autoantibodies. We propose that the unusually high affinity of O1 and O4 to their targets in myelin contributes to the mechanism by which they signal oligodendrocytes and induce central nervous system repair.
  Analytical Chemistry 07/2012; 84(14):6031-9. · 5.86 Impact Factor
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  Article: Catalytic antibodies: Concept and promise

  Desirazu N. Rao, Bharath Wootla
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  ABSTRACT: While chemistry provides the framework for understanding the structure and function of biomolecules, the immune system provides a highly evolved natural process to generate one class of complex biomolecules-the antibodies. A combination of the two could be exploited to generate new classes of molecules with novel functions. Indeed, one example of this productive interplay is the generation of catalytic antibodies or abzymes. A catalytic antibody is a sort of natural artificial enzyme — it is a natural protein synthesized by the usual biological processes and is intended to catalyze a reaction for which no real enzyme is available. The essential idea is to raise antibodies to a molecule considered to mimic the transition state intermediate of a reaction that is to be catalyzed i.e., a molecule resembling a strained structure intermediate between the substrate and product, believed to occur in the reaction pathway. The hope is that some of the antibodies produced will happen to possess groups capable of promoting the reaction.
  Resonance 04/2012; 12(11):6-21.
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  Available from: Bharath Wootla

  Article: Need for a paradigm shift in therapeutic approaches to CNS injury.

  Bharath Wootla, Aleksandar Denic, Arthur E Warrington, Moses Rodriguez
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  ABSTRACT: Irreversible damage to the nervous system can result from many causes including trauma, disruption of blood supply, pathogen infection or neurodegenerative disease. Common features following CNS injury include a disruption of axons, neuron death and injury, local B-cell and microglial activation, and the synthesis of pathogenic autoantibodies. CNS injury results in a pervasive inhibitory microenvironment that hinders regeneration. Current approaches to eliminate the inhibitory environment have met with limited success. These results argue for a paradigm shift in therapeutic approaches to CNS injury. Targeting CNS cells (neurons, oligodendrocytes and astrocytes) themselves may drive CNS repair. For example, our group and others have demonstrated that autoreactive antibodies can participate in aspects of CNS regeneration, including remyelination. We have developed recombinant autoreactive natural human IgM antibodies with the therapeutic potential for CNS repair in several neurologic diseases.
  Expert Review of Neurotherapeutics 04/2012; 12(4):409-20.