Kostantin Dobrenis

Our principal interests lie in the therapy of neurologic diseases and in the field of glial neurobiology. Much of our work has focused on developing effective therapeutic strategies for neuronal storage disorders such as Tay-Sachs disease. The goal here is to find effective means of replacing the lysosomal enzymes that are genetically deficient in these diseases. A current line of investigation stems from studies demonstrating that bone marrow transplantation can treat the central nervous system (CNS) in one storage disease, (-mannosidosis. We are now attempting to delineate the critical cellular mechanisms, responsible for this success. Our studies to date have indicated the importance of donor-derived microglia, their secretion of lysosomal enzymes and neuronal uptake mechanisms in obtaining therapeutic efficacy. Insights gained are helping to direct improvement of clinical strategies for related disorders as yet untreatable.

A new major goal is the development of a novel approach for the treatment of CNS aimed at overcoming the hurdle posed by the blood-brain barrier to potential therapeutic agents. Cell lines from unique transgenic animals are being developed with both brain-targeting and secretory properties to serve as safe and effective vectors for the delivery of such agents from the circulation to neurons within the CNS. This approach may be applicable to a wide variety of diseases with global CNS involvement for which current delivery modalities are inadequate.

Our interest in non-neuronal populations of the CNS has focused in recent years on microglia. The biology of this cell type is relatively unexplored territory. Our projects have included the discovery of the presence a novel opiate receptor in mammalian microglia and astrocytes, and evidence for immediate microglial responses to neuronal injury.

Our experimental approach is largely at the level of cell biology but extends to biochemistry, molecular genetics, histology and transplantation. Cultures of CNS cell populations from different species together with immunocytochemical techniques are used extensively. State-of-the-art approaches utilizing fluorescent probes and real-time laser confocal microscopy are also employed to monitor molecular and subcellular changes in living cells.

Selected Publications