Director Translational Research Center, Massachusetts General Hospital

Physician Lipid Metabolism, Massachusetts General Hospital

Clinicn Investigator, Full Prf Lipid Metabolism, Mass General Research Institute

Professor of Medicine Harvard Medical School

MD UC San Francisco School of Medicine 1979

antigens, cd36; apolipoprotein a-i; atp-binding cassette transporters; cholesterol; macrophages; receptors, immunologic

The Freeman laboratory’s research centers on the role of lipid transport mechanisms, particularly into and out of macrophages, and the contribution those processes make to human disease.

The emphasis has historically been on atherosclerosis. Atherosclerosis manifests as coronary artery disease as well as peripheral vascular disease and these two vascular disorders account for much of the morbidity and mortality associated with diabetes. At the same time, diabetes is a major risk factor for the development of accelerated atherosclerosis.

The macrophage plays a critical role in the initiation of atherosclerotic plaques and increasing evidence suggests that macrophages also contribute to complex lesion development and plaque rupture.

Genetically engineered mice are employed by our laboratory to examine the role of macrophage receptors that bind modified forms of lipoproteins, leading to atherosclerotic foam cell formation. As glycated lipoproteins have also recently been demonstrated to bind to these macrophage scavenger receptors, their role in diabetic atherosclerosis may be significant. LDL receptor deficient and apo E deficient mice in the C57/BL6 background form atherosclerotic lesions in the proximal aorta that share many characteristics of human atheroma. Early foam cell lesions followed by the development of complex, calcific plaques are generated in these animals. Recent studies have been examining the following questions:

Is scavenger receptor uptake of modified lipoproteins essential for lesion formation and progression? This issue is addressed through the generation of mice lacking the two major scavenger receptors known to be expressed in atherosclerotic lesions (i.e., SR-A, and CD 36). Knock-outs for both receptors are in hand and our initial work has indicated that while the receptors are not required for foam cells to form in hyperlipidemic mice, they do appear to contribute to the inflammatory and apoptotic responses that are generated in the artery wall of the animals.

We also recently identified an important role for the innate immunity signaling pathways that link through the toll receptor adaptor molecule known as MyD88 and work is ongoing to explore the role of these pathways in atherosclerosis. Finally, lipid egress mechanisms are being examined through a detailed structure/function analysis of ABCA1 and other members of the A class of ABC transporters and through this work we have identified major lipid transport functions that affect skin integrity and respiratory function.