Grant: Operating Grant

In the past decade, my colleagues and I have discovered and studied a group of important proteins called histone deacetylases. These proteins are important regulators able to control the way by which the genetic material is organized in human cells. Like genetic mutations, abnormal organization of the genetic material has recently been recognized as oneimportant reason for various human diseases, including cancer. Clinical trials with chemical compounds that are able to inhibit the activities of these regulators have yielded very promising results. For example, one such compound (now known as Zolinza, Merck) was approved as the first histone dacetylase-based drug, for treating cutaneous T-cell lymphoma. One problem with these compounds is serious toxicity or side effects. To develop agents able to target different histone deacetylases more selectively and precisely, it is necessary to understand the function and regulation of these regulators themselves. In this grant application, we propose to continue our studies of these important proteins, by carrying out molecular and genetic analyses of a subgroup of such regulators. Our recent results identified modulators of the histone deacetylases. Excitingly, this modulator is directly linked to lung cancer and the Peutz-Jeghers syndrome (a genetic disease characterized by the development of benign polyps and other tumor-like growth in the gastrointestinal tract), so the proposed studies shall yield new insight into the molecular basis of cancer and other human diseases. This is one of the very first steps towards developing new methods of diagnosis and therapy. Compounds able to inhibit histone deacetylase activity have been isolated from garlic, broccoli and fruits, and there are animal studies indicating that physical exercise regulates the activity of histone deacetylases. Therefore, the proposed studies shall also shed light on how to adjust diet and life style for disease prevention.