Dr. Tracy Handel: Structural Biology of Chemokines/Receptors and Their Role in Disease

Research Summary: Structural Biology of Chemokines/Receptors and Their Role in Disease

Dr. Handel's research is focused on the relationship between structure and function of proteins, with an emphasis on chemokines and chemokine receptors. These proteins control the migration of cells in the context of development, immune surveillance, and inflammation. However, inappropriate utilization or regulation of chemokines/receptors is also associated with numerous diseases including inflammatory disease, atherosclerosis, cancer, HIV, and malaria. In the structural arena, there are several areas of study: (i) Chemokine interactions with glycosaminoglycans which are carbohydrates found on all cell surfaces. These interactions control the localization and transport of chemokines and are critical to the function of these proteins; (ii) Development of protein therapeutics that function as receptor antagonists; (iii) Structural studies of chemokine receptors which are G protein-coupled receptors; (iv) Analysis of the interaction of chemokine receptors with their intracellular signaling partners. For these efforts, the laboratory utilizes a variety of techniques including X- ray crystallography, NMR, BRET/FRET, H/D exchange mass spectrometry, other biophysical methods, cell based assays, molecular biology, phage display, and protein expression in a variety of heterologous systems. A second area of interest is the role of chemokines/receptors in cancer, particularly breast cancer and chronic lymphocytic leukemia (CLL). In breast cancer, specific chemokine receptors have a variety of roles including metastasis, tumor growth and proliferation, and angiogenesis. In CLL, chemokines/receptors provide survival signals that contribute to the aggressiveness of the disease. The laboratory studies the signal transduction mechanisms induced by chemokines in an effort to identify how the receptors are reprogrammed in the context of cancer cells and to identify potential new therapeutic targets.

Academic Achievements

Education: B.S. in Chemistry (1980) Bucknell; Ph.D. in Chemistry (1989) Caltech. Postdoc in Biophysics (1989-92) Dupont Merck Pharmaceuticals.

Awards and Honors: Caltech McKoy Award for Excellence in Graduate Research (1988); Long Term Incentive Award at DuPont Merck (1993); Highest Relative Performance Rating at Dupont Merck (1993); NSF Young Investigator Award (1994); Pew Scholars Award (1995); Hellman Fellows Award (1996); Berkeley Research & Teaching Award (2000).

Leadership Experience: UCSD: SSPPS Faculty Chair (2008-), Vice Chair Biomedical Sciences Program (2008-), Chair Biomedical Sciences Admissions Committee (2006-2009, 2011-), Oversight of SSPPS NMR Facility, Health Sciences Research Council (6/2005-), Health Sciences Faculty Council (6/2007-). UC Berkeley: Elected Chair, Biophysics Program (Fall 2004-2005).

Teaching

• Pharmaceutical Biochemistry (SSPPS 223, Course Director).
• Contemporary Topics in Pharmacology (SSPPS 218B).
• Structural and Quantitative Pharmacology (Biom 230, Course Director).
• Molecules to Man (Biom 200).

Key Contributions to Pharmaceutical Sciences

• Revealed complex structure-function relationships in chemokine-receptor interactions.
• Discovered several novel mechanisms of receptor antagonism based on modified chemokine. Developed novel methods to select for high affinity chemokine antagonists.
• Discovered novel mechanisms by which chemokines contribute to cancer, and the potential of small molecule inhibitors for CLL.
• Developed methods for expression of chemokine receptors for structural studies.

Selected Recent Publications (from 93 peer reviewed articles)

Handel et al. (2008). An Engineered Monomer of CCL2 has Anti-inflammatory Properties Emphasizing the Importance of Oligomerization for Chemokine Activity In Vivo. J of Leukocyte Biology 84:1101-8.

O'Hayre et al. (2008). Chemokines and Cancer: Migration, Intracellular Signaling, and Intercellular Communication in the Microenvironment. Biochemical J. 409:635-49.

Allen et al. (2009). Expression, Purification and In Vitro Functional Reconstitution of the Chemokine Receptor CCR1. Protein Expression and Purification. 66:1-6.