To define the role of chemoattractants and their receptors in leukocyte development, immune surveillance, and immune dysregulation (allergy, autoimmunity, and inflammatory disorders).
Public Health and Military Service Member-Targeted Research:
To discover and develop novel therapeutics (small molecules, peptides, monoclonal antibodies) to treat allergy, autoimmune diseases, inflammatory disorders, and cancer.
Chemoattractants and Receptors
Leukocyte chemoattractants are a structurally diverse collection of bioactive molecules that includes lipids (e.g. leukotrienes, sphingosine 1 phosphate, and prostaglandin D2), peptides (e.g. chemerin nonamer and formyl-methionyl-leucyl-phenylalanine (fMLP)), and small proteins of several classes (e.g. chemokines, defensins, “cystatin-like” fold possessing attractants like chemerin, and non-chemokine cytokines (such as stem cell factor)). While all of these molecules are less than 20 kD, individual members can differ ~50-fold in size (e.g. chemerin is ~16,000 Da, while leukotriene B4 (LTB4) is 337 Da). Each attractant binds to one or more receptor of the serpentine, or seven-transmembrane spanning G protein coupled receptor (GPCR) superfamily (although not all receptors necessarily couple to G proteins). Chemoattractants and their receptors are highly regulated both developmentally and during inflammatory and immune responses, and play critical roles in the development and function of the immune (and other) systems. Selective leukocyte homing via chemoattractant:receptor interactions is essential to the overall organization of the immune system and subsequent protection against infectious disease. Importantly, chemoattractants can also play a pathogenic role in exacerbating allergic responses, autoimmune disease, or other inflammatory disorders.
Orphan Heptahelical Receptors
Orphan receptors are DNA sequences that share significant homology with known leukocyte chemoattractant receptors, yet remain uncharacterized with respect to ligand-binding properties and functions. Leukocyte-expressed orphan receptors represent excellent candidates for additional regulators of immune cell trafficking and function. Identifying ligands for non-signaling orphan serpentine receptors is particularly challenging, since the assays employed in most heptahelical receptor ligand screens depend on functional responses, such as intracellular calcium mobilization or cell migration. We ‘de-orphaned’ three receptors to date: CCR9 (which binds CCL25), CMKLR1 (which binds chemerin), and CCRL2 (which also binds chemerin). We also worked on the initial functional characterization of CXCR7 (which binds CXCL12 and CXCL11).
For more information on the role of chemoattractant receptors in human disease pathogenesis, I am pleased to provide you complimentary one-time access to my Annual Reviews article as a PDF file (http://arjournals.annualreviews.org/eprint/tCdHiuVIkZjPg6pgxTvD/full/10.1146/annurev-pathol-012513-104640) for your own personal use. Any further/multiple distribution, publication, or commercial usage of this copyrighted material requires submission of a permission request addressed to the Copyright Clearance Center (http://www.copyright.com/).