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Our laboratory is interested in elucidating the molecular basis of human disease and in using this information to guide development of new and safer therapies. We utilize state of the art technologies, including genetics, genomics, biochemistry, cell biology, structural and computational biology and animal models of disease.
Cells exist in a highly dynamic extracellular milieu consisting of complex chemicals and mechanical stress signals to which cells must continuously adjust and in turn moderate. In metazoa, the task of integrating these mechanochemical cues across the plasma membrane is divalent-cation-dependent and is mediated by integrins, αβ heterodimeric type I membrane receptors. Integrins are normally expressed in a low affinity state, but rapidly and reversibly switch into high affinity by agonists, which act on the integrin cytoplasmic tails to modify their affinity to extracellular ligands (so-called inside-out activation). Ligands bind activate integrins eliciting classic "outside-in" signals that regulate every aspect of cell function. We have identified a human disease, leukocyte adhesion deficiency, in which a sub-group of integrins, b2 integrins, is lacking. The affected patients suffer from life-threatening bacterial infections. Loss of other integrins causes bleeding diathesis or organ malformations. Improper activation of integrins on the other hand is associated with common inflammatory and metabolic disorders including atherosclerosis, diabetes, and cancer metastasis. A major effort in our laboratory is to understand the structural basis of integrin activation and signaling using biochemical, structural and animal models. A potential outcome is the discovery of small molecule antagonists to treat common diseases linked to integrin dysfunction.
ADPKD is the most common monogenic disease in humans, caused by dysregulation in diameter of tubular structure including kidney tubules and blood vessels leading chronically to loss of renal function or cutely to cerebral hemorrhage due to ruptured vascular cysts. We have generated a mouse KO of ADPKD and demonstrated that one of the two defective genes, PKD2, encodes a TRP-like calcium channel, which is stabilized by the product of the second gene, PKD1. We have identified a transcriptional modulator of PKD1, which causes pronephric cysts when knocked down in zebrafish. Biochemical and cell biology approaches are being used to elucidate the pathway linking this modulator to cystogenesis in zebrafish and mouse models. Other work attempts to elucidate the signaling pathways involved in determining tube diameter.
This is a new area of investigation in my laboratory, driven initially by serendipitous findings I made while pursuing aspects related to integrins. We found that a zinc finger transcription factor, which regulates ab2 integrin in mature leukocytes, appears to regulate developmental fate of hemangioblasts, the precursors of hematopoietic and vascular stem cells. Work is ongoing to define how each lineage is regulated by this factor at the transcriptional level and the interacting proteins involved using embryonic stem cell/embryoid body cultures, siRNA, and zebrafish and conditional mouse KO models.
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