Dandan Sun, M.D., Ph.D.

As a scientist, my philosophy in research is to conduct investigation in important, unexplored biology areas and discover scientific findings that will advance our knowledge in general. Specifically, we have chosen areas that have potential significance to bridge the gap between basic science development and clinical application. Currently, our research goal is to investigate the molecular mechanisms underlying ischemic brain damage and gain knowledge in order to facilitate developing therapeutic treatments of stroke. In recent years, our focus is on understanding of ion homeostasis, particularly a role of Na-K-Cl cotransporter isoform1 (NKCC1), in the central nervous system (CNS) under physiological and ischemic conditions.
NKCC1 transports a net influx of Na+, K+, and Cl- in cells under physiological conditions. NKCC1 has been extensively studied in epithelium for salt secretion and reabsorption. However, a role of NKCC1 in the CNS has not yet been fully understood.

1. Our original studies suggest that NKCC1 is important in regulation of intracellular Cl- concentration ([Cl-]i) in immature neurons and loss of intracellular Cl- via GABA receptor-channel enhances NKCC1 activity (Sun and Murali, 1999). Thus, NKCC1 function is essential to maintain a high [Cl-]i than equilibrium that results in GABA-mediated Cl- efflux and depolarization. GABA and glycine are the main inhibitory neurotransmitters in the adult mammalian CNS. In fetal and postnatal development, both neurotransmitters are mostly excitatory because [Cl-]i is above equilibrium. The excitatory action of GABA in the immature CNS is important for the development of the nervous system.



2. In addition, we found that activation of glutamate receptors also stimulates NKCC1 activity in neurons (Sun and Murali, 1998, Schomberg, et al., 2001, 2003). The significance of these findings is that NKCC1 and NKCC1-mediated Cl- influx could associate with a synergistic excitatory action of GABA and glutamate during neuronal maturation and differentiation.



3. NKCC1 is also important in K+ uptake in astrocytes. We reported a comprehensive characterization of NKCC1 expression and NKCC1 activity in astrocytes (Yan, et al., 2001, Su et al., 2000). In our recent studies using pharmacological and transgenic knockout approaches, we demonstrated that NKCC1 contributes to astrocyte swelling and glutamate release under elevated K+ conditions (Su et al., 2002a, 2002b).



4. The findings described above suggest that NKCC1 could play a role in cell swelling and alteration of ion homeostasis in cerebral ischemia and neuron damage. We found that inhibition of NKCC1 activity pharmacologically significantly reduces edema and infarct volume (Yan et al., 2001, 2003). We are currently investigating cellular mechanisms underlying NKCC1-mediated neuronal cell death and its association with ion homeostasis changes. Our in vitro study suggests that activation of NKCC1 activity contributes to excitotoxicity in neurons (Beck et al., 2003).

Model of Na-K-Cl cotransporter Isoform 1 Protein