Israel F. Charo, M.D., Ph.D.
Associate Director and Senior Investigator
Gladstone Institute of Cardiovascular Disease
Professor of Medicine
University of California, San Francisco
Email: icharo@gladstone.ucsf.edu
Telephone: 415-734-2713
Fax: 415-355-0960

Focus
Chemokines (chemotactic cytokines) are secreted proteins that regulate the trafficking of leukocytes in the body. Our laboratory is involved in understanding the role of chemokines in the pathogenesis of a wide range of human diseases, particularly vascular disease, and in the regulation of the immune response.

Significance
Leukocyte migration is a fundamental component of normal physiology, and chemokines govern much of this movement. The constitutive trafficking of lymphocytes from the blood through secondary lymphoid organs and the movement of neutrophils and monocytes to sites of inflammation are regulated by spatial and temporal expression of chemokines. The specific leukocytes that respond to these chemokines are, in turn, determined by the complement of chemokine receptors that each cell expresses. Recent work has revealed key roles for chemokines in the pathogenesis of diseases such as atherosclerosis, AIDS, and cancer metastases. Recent intense efforts to develop antagonists to chemokines and their receptors have provided scientists with new tools for understanding the biology of chemokines.

Approaches
We use a variety of approaches, including basic molecular biology for structure-function studies, cell biology techniques for investigating stimulus-response coupling, and DNA microarray techniques for RNA profiling. We have made a number of mouse models in which genes for chemokines and their receptors have been deleted or knocked out. Much of our work uses these novel genetic models to understand the roles of chemokines in the whole animal. Our overall goal is to further our understanding of the roles of chemokines in human disease.

Contributions
Our group was the first to clone the gene for CCR2, the receptor for monocyte chemoattractant protein-1 (MCP-1) and the first to make a knockout mouse model of CCR2. We demonstrated that CCR2-deficient mice are protected in murine models of atherosclerosis because they fail to recruit monocyte/macrophages into the blood vessel wall. We also cloned CCR5 and were among the first to show its critical role in the uptake of HIV-1 by host cells. We created a fractalkine receptor knockout mouse and showed that this chemokine plays an important role in the rejection of transplanted organs. Our most recent work has focused on understanding the roles of chemokines in the adaptive immune response and in affording protection against infectious diseases, such as Mycobacterium tuberculosis.

Questions we are currently investigating include:

• What is the role of CCR2 in established atherosclerotic lesions?
• Will blocking CCR2 lead to regression of complex, advanced atherosclerotic lesions?
• How do chemokines such as MCP-1 and other CCR2 agonists regulate polarization of T cells?
• Can one use conditional expression of reporter genes in transgenic mice to study macrophage trafficking in vivo?
• Are there other receptors for MCP-1?

Selected References

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