David W. Russell

My laboratory studies the metabolic pathways that cells use to break down cholesterol. Various tissues, including the liver, skin, prostate, and brain, utilize different enzymes to metabolize cholesterol. In the liver, we isolated 8 of the 16 enzymes that convert cholesterol into bile acids and identified the molecular bases of three inherited forms of liver failure in humans. In the skin, we purified the enzyme that produces 25-hydroxyvitamin D3, the major circulating form of vitamin D in the blood, and showed that mutations in this gene cause rickets. In the prostate, we identified two genes that synthesize the potent male hormone dihydrotestosterone. Mutations in one of the encoding genes cause male pseudohermaphroditism, and drugs that inhibit both enzymes are used to treat prostatic disease and baldness. In the brain, we isolated the enzyme responsible for the majority of cholesterol turnover, cholesterol 24-hydroxylase. Loss of this brain-selective enzyme in the mouse reduced cholesterol turnover, which unexpectedly led to learning deficits and decreased synaptic plasticity. Currently, we are elucidating the neurobiological mechanism by which alterations in cholesterol turnover affect learning and memory and we are developing chemical methods to identify novel lipids and their biological roles in mammalian cells.