Michael R. Freeman, Ph.D.
David E. Retik Director of Basic Urologic Research
Children's Hospital Boston
Professor of Surgery
Harvard Medical School

John F. Enders Research Laboratories
Suite 1161
300 Longwood Avenue
Boston, MA 02115
617-919-2644 (office)
617-730-0238 (fax)
michael.freeman@childrens.harvard.edu

My research group focuses on studies directed toward understanding the molecular basis of genitourinary tract pathology of several kinds. We primarily study diseases involving the bladder, prostate and kidney.

We have a long history investigating the function and regulatory features of the ErbB receptor tyrosine kinase ligand, heparin-binding EGF-like growth factor (HB-EGF), in a variety of contexts. In the lower urinary tract, our observations suggest that HB-EGF participates in “hypertrophic” changes, such as tissue expansion, thickening, and degeneration, in the bladder’s muscle layers. These phenomena are associated with debilitating and painful syndromes in children and adults, such as urinary tract obstruction, interstitial cystitis and benign prostatic hyperplasia. We are now studying the intracellular signaling systems that regulate bladder and ureteral smooth muscle cell growth using in vitro and in vivo approaches. In addition to its role as a regulator of muscle growth, HB-EGF is a prostate cancer cell mitogen and survival factor synthesized by interstitial smooth muscle cells of the human prostate stroma. This location and other recently acquired data suggest that HB-EGF is one of the long-hypothesized stromal mediators of prostate epithelial cell function.

Another area of interest involves the study of the mechanisms of signal processing through specialized cell membrane domains, called lipid rafts, in prostate cancer and urinary tract smooth muscle cells. We recently identified membrane cholesterol as an important regulator of the PI3K/Akt/mTOR signaling pathway, a signal transduction mechanism that is thought to be functionally involved in regulation of tissue size and in human prostate cancer progression. Our findings suggest a new explanation for the epidemiological link between prostate cancer and a diet rich in animal products or fat. Model systems currently in use in the lab to study this membrane microdomain include in vitro and ex vivo systems, mouse-human tumor xenografts and zebrafish.

A third area involves the study of the function of the calcium entry channel, CaT1, in epithelial cell physiology and malignant growth. In recent reports, we have described the first link between this selective ion channel and human prostate cancer and other malignancies, and have provided evidence that CaT1 is the major portal of calcium entry in the gastrointestinal tract epithelium.

These studies, which are funded by the National Institutes of Health and the US Department of Defense, are directed toward our goal of translating fundamental insights into the basic biology of the genitourinary tissues into improvements in treatment of urologic disease.

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