FUNDAMENTAL AND FUNCTIONAL ASPECTS OF NA/H EXCHANGE

Project: Research project

Project Details

Description

The focus of this laboratory has been on the roles played by alkali metal/H exchange in cell volume and pH regulation and disturbances. Studies proposed in the present application are extensions of these interests and represent attempts to; 1) investigate alkali metal/H exchanger identity and control employing the Amphiuma red blood cell as a model system (fundamental/mechanistic studies) and ; 2) employ NMR spectroscopy and Langendorff perfused heart to continue our investigation of the role(s) played by pH regulatory Na/H exchange as a contributor to hypoxic and ischemic injury (functional studies). In addition we will extend and refine the heart studies to include other transport pathways which interact with the Na/H exchanger during hypoxia and ischemia. With regard to the studies of the Amphiuma RBC we will test what we feel is an exciting hypothesis that alkali/metal/H exchange and Na-K ATPase activity in Amphiuma RBCs are controlled by vesicular insertion and removal. If, as suggested by our preliminary data, membrane trafficking is employed by the Amphiuma RBC as a means of controlling transport activity, then our studies will establish a new paradigm for evaluating inducible transport processes. We will also determine the molecular identity of the Na/H exchanger and test the hypothesis that the Na/H and K/H functions in Amphiuma RBCs are mediated by the same molecular entity. The studies to be performed using Langendorff perfused hearts will apply principles developed in our studies of Amphiuma RBC volume and pH regulation, as they relate to the control of the Na/H exchanger as a contributor to cytotoxic edema, consequent to hypoxic and ischemic insult. Additionally, we will evaluate the interaction of the Na/H exchanger with other transport pathways which contribute to hypoxic and ischemic cell damage (i.e. Na/Ca and C1/HC03 exchangers and the Na+K=2C1 cotransport). We will test the hypothesis that (as we have shown in the Amphiuma RBC) there is hierarchial signal prioritization such that volume can override pH. That is if cells are shrunken prior to acidification (such as occurs during hypoxic and ischemic episodes) the Na/H exchanger is unresponsive to decreased pHi and responds only to volume. We hypothesize that this characteristic may be the basis for the benefits resulting from hypertonic saline resuscitation. In light of the above we will characterize the volume regulatory response of the in situ cardiomyocyte and identify the relevant ion flux pathways. finally, we will test the hypothesis that net influx by the Na=K+2C1 cotransporter functionally coupled (via [C1]i) to the C1/HC03 exchanger leads to intracellular alkalinization which is at the basis for the protective effects of ischemic preconditioning (PC-Lawson and Downey, 1993).
StatusFinished
Effective start/end date4/1/7811/30/05

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $584,688.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $511,464.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $550,039.00
  • National Institutes of Health: $530,114.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $567,658.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

ASJC

  • Medicine(all)

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