Lab Research Focus
The main goal of my research is to define the development and differentiation of lymphoid-and myeloid-lineage cells in the context of exploring the diseases of the immune system. Several cell surface molecules expressed by these cell types are being studied with regard to their structure and function in adaptive and innate immunity. In particular, my colleagues and I are currently focusing on paired immunoglobulin-like receptors, PIR-A (A for activating) and PIR-B (B for braking or inhibitory), which have recently been discovered in my laboratory. PIR-A and PIR-B are encoded respectively by multiple PIR-A genes and a single PIR-B gene in mice and relatives of the activating and inhibitory receptors on human NK cells. PIR-A and PIR-B genes encode type I transmembrane proteins with similar ectodomains (>92% homology), but distinctive transmembrane and cytoplasmic regions. The predicted PIR-A protein contains a short cytoplasmic tail and a charged arginine residue in its transmembrane region, suggesting possible association with additional transmembrane proteins to form a signal-transducing unit. In contrast, the PIR-B protein has a typical uncharged transmembrane region and a long cytoplasmic tail with multiple candidate immunoreceptor tyrosine-based inhibitory motifs (ITIMs). Another intriguing difference is that the PIR-A receptors display sequence diversity in their ectodomains. PIR-A and PIR-B expression is restricted to B cells and myeloid-lineage cells (i.e., monocyte/macrophages, granulocytes, mast cells), wherein both genes are coordinately or "paired" expressed. The PIR genes are conserved in humans, rats and chickens, suggesting an ancient gene family. These features thus suggest that PIR-A and PIR-B encode receptor proteins having related ligand-binding specificity, but different intracellular signaling properties. In order to test the hypothesis that PIR-A and PIR-B play important regulatory roles in humoral, inflammatory and allergic responses, the following studies are underway:
- Produce monoclonal antibodies against shared and distinctive epitopes on PIR-A and PIR-B molecules and use these antibodies to determine i) their cellular distribution and relative expression levels and ii) their structure and unit composition.
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- Examine the functional potential of the ITIMs in the PIR-B molecule and the effects of PIR cross-linkage on B cell and macrophage responses.
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- Isolate and sequence genomic PIR-A and PIR-B clones to determine the genetic basis for the sequence diversity of the PIR-A genes.
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- Prepare a PIR-B deficient mouse to define PIR function in vivo.
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- Determine the PIR-A clonal repertoire for B cell and myeloid lineage cells.
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- Identify the PIR ligand(s).
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