The Department of Molecular Genetics is home to several internationally recognized scientists.
Brown and Goldstein
Drs. Joseph L. Goldstein and Michael S. Brown, who received the U.S. Medal of Science in 1988, shared the Nobel Prize in Physiology or Medicine in 1985 for their discovery of the LDL receptor and the underlying mechanisms of cholesterol metabolism.
Their Nobel Prize-winning findings led to the understanding and development of statin drugs, the cholesterol-lowering compounds that today are used by 16 million Americans and the most widely prescribed medications in the United States. New federal cholesterol guidelines will triple the number of Americans taking statin drugs to lower their cholesterol, reducing the risk of heart disease and stroke for countless people.
Drs. Brown and Goldstein’s discovery of the LDL receptor revealed the biological process of Receptor-mediated Endocytosis and led to the identification of the molecular defect in Familial Hypercholesterolemia, an inherited disorder that predisposes to early heart attacks and affects 1 in 500 people throughout the world.
Today, the Brown-Goldstein laboratory is working in three metabolic areas: 1) the SREBP pathway for control of lipid synthesis; 2) the NPC2-NPC1 hydrophobic handoff pathway for cholesterol transport in lysosomes; and 3) the Ghrelin-Growth hormone axis for control of blood glucose during starvation.
The laboratory of Russell DeBose-Boyd, Ph.D., who was appointed a Howard Hughes Medical Institute Early Career Scientist in 2009, focuses on the regulation of HMG CoA reductase. HMG CoA reductase produces mevalonate, a crucial intermediate in the synthesis of cholesterol. Inhibitors of HMG CoA reductase, collectively called statins, have revolutionized the treatment of high blood cholesterol levels in humans. Statins trigger effects that result in the decrease of blood cholesterol, thereby reducing the incidence of heart attacks. The deficiency in mevalonate-derived products that accompanies statin therapy triggers a compensatory increase in HMG CoA reductase protein, invoking the need for higher doses of the drug to maintain cholesterol-lowering effects. Understanding the mechanisms for this compensatory increase in HMG CoA reductase may lead to development of novel therapies that potentiate the therapeutic effectiveness of statins.
Alzheimer’s disease and atherosclerosis are progressive degenerative syndromes that together afflict more than 50 percent of the population in Western societies. Joachim Herz, M.D., Director of the Center for Alzheimer’s and Neurodegenerative Diseases at UT Southwestern, has identified several fundamental molecular mechanisms that are common to both of these superficially unrelated diseases. His lab uses refined conventional and conditional gene targeting and transgenic approaches in mice to investigate the molecular basis on which LDL receptor family members control pivotal mechanisms of cellular communication during embryonic development and in the adult organism.
Helen H. Hobbs, M.D., is Director of the Eugene McDermott Center For Growth and Development / Center for Human Genetics. The central theme of her research program is how dysregulation in the uptake and trafficking of dietary lipids contribute to human diseases, in particular coronary atherosclerosis and the metabolic syndrome. We recently identified sequence variations in a circulating protein, a member of the proprotein convertase gene family called PCSK9, that are associated with lower plasma levels of LDL-cholesterol and protection from heart disease. The mechanistic studies in the laboratory are complemented by family and population-based studies in humans to examine the effects of sequence variations in the genes we identify on plasma sterol levels and risk for heart disease.
Dr. Jay D. Horton, M.D., focuses his research on determining the molecular sequence of events that lead to hepatic steatosis, steatohepatitis, and cirrhosis. Investigations from the laboratory have revealed how the primary transcriptional regulators of cholesterol metabolism (sterol regulatory element binding proteins) are also key regulators of fatty acid synthesis and composition in liver. A major goal of his laboratory is to determine how these transcriptional regulators contribute to the development of steatosis in various disease processes such as diabetes, obesity, and beta-oxidation defects. A second area of investigation centers on determining the function of PCSK9, a protein that is involved in determining plasma LDL cholesterol levels through its ability to post-transcriptionally regulate the expression of the LDL receptor in liver.
Arun Radhakrishnan, Ph.D., focuses his research on how cholesterol is organized in membranes and how this organization modulates its interaction with proteins. Using biophysical techniques to study the interaction of soluble cholesterol-binding bacterial toxins with model membranes, we hope to shed light on the underlying molecular mechanisms governing cholesterol sensing and transport.
Drs. Goldstein, Brown, Yanagisawa, Hobbs, and David W. Russell are members of the National Academy of Sciences. Dr. Russell’s research uses the techniques of molecular biology, genetics, and whole-animal physiology to study the regulatory actions of crucial molecules derived from the sterol nucleus. These molecules include androgenic hormones, bile acids, vitamin D, and hydroxylated steroids. In recent years, his laboratory has discovered the genetic basis of six human diseases in which these pathways are disrupted, including rickets, failure of male development (male sex reversal), and fatal neonatal jaundice.
Early in his career, Howard Hughes Medical Institute investigator and professor Dr. Masashi Yanagisawa made several key discoveries about endothelins, proteins that constrict blood vessels and raise blood pressure. At least three drugs have now been found to block endothelins. Ten years later, he and his colleagues discovered a protein that boosts hunger, which they named orexin. Orexin also proved to play a key role in sleep—mice lacking orexin developed narcolepsy. Clinical researchers have since shown that about 95 percent of people with narcolepsy lack the ability to produce orexin. Dr. Yanagisawa’s group is working on potential drugs to treat narcolepsy and better control the sleep-wake cycle.
Jin Ye, Ph.D., focuses his research activities on host factors required for Hepatitis C Virus (HCV) infection. His lab recently revealed that cholesterol metabolism in host cells is tightly linked to the life cycle of HCV. They showed that HCV RNA replication can be disrupted by treatment of cells with lovastatin, a cholesterol lowing drug that inhibits 3-hydroxy-3-methylglutaryl CoA reductase, the rate-limiting enzyme in a pathway responsible for the cholesterol synthesis in mammalian cells. Another link between HCV infection and cholesterol metabolism in host cells is revealed by our recent discovery that HCV replicates on membrane vesicles involved in the assembly of very low density lipoproteins (VLDL), which is produced in hepatocytes to secret triglyceride and cholesterol.
Tenured Faculty Members
Joseph L. Goldstein, M.D.
Professor and Chair
Michael S. Brown, M.D.
Russell DeBose-Boyd, Ph.D.
Joachim Herz, M.D.
Professor and Director
Center for Alzheimer’s and Neurodegenerative Diseases
Helen H. Hobbs, M.D.
Professor and Director
Eugene McDermott Center for Human Growth and Development
Jay D. Horton, M.D.
Arun Radhakrishnan, Ph.D.
David W. Russell, Ph.D.
Masashi Yanagisawa, M.D., Ph.D.
Jin Ye, Ph.D.
Sarah Comerford, Ph.D.
Murat Durakoglugil, M.D., Ph.D.
Yiu Kee Ho, Ph.D.
Guosheng Liang, Ph.D.
Jeffrey G, McDonald, Ph.D.
Young-ah Moon, M.D., Ph.D.
Toshiyuki Motoike, M.D., Ph.D.
Robert B. Rawson, Ph.D.