The J. David Gladstone Institutes

Series: Molecular Medicine Institutions

Robert W. Mahley, M.D., Ph.D., President Affiliated with the University of California, into six units: the Lipoprotein Metabolism and San Francisco (UCSF), and located on the San Biochemistry Unit, the Cell Biology Unit, the Francisco General Hospital (SFGH) campus, the Molecular Biology Unit, the Vascular Biology J. David Gladstone Institutes have become rec- Unit, Clinical Molecular Genetics Unit, and the ognized worldwide for research into the causes new Molecular Neurobiology Program. and prevention of three critically important dis- By applying a multidisciplinary approach to eases of our time: cardiovascular disease, AIDS, the study of lipid metabolism, integrating bio- and Alzheimer's disease. chemistry, molecular biology, cell biology, phys- The Institutes-Gladstone Institute of Car- iology, and population genetics, the Institute has diovascular Disease and Gladstone Institute of achieved an international reputation for its con- Virology and Immunology (Fig. 1)-are orga- tributions to the field of cardiovascular research. nized as a charitable trust created under the will Since 1979, more than 600 articles and book of J. David Gladstone, a prominent southern Cal- chapters from the Institute have been published, ifornia real estate developer. Mr. Gladstone be- including seminal publications on two major fac- queathed virtually his entire estate to establish tors involved in lipoprotein metabolism and scholarships for medical students and to fund atherogenesis, apolipoprotein (apo-) E and medical research. Through inspired manage- apo-B. Among their scientific accomplishments, ment, the Gladstone Trustees [Richard S. Braw- Institute scientists have determined the struc- erman, Albert A. Dorman, David Orgell (de- tures of both of these proteins and their genes; ceased), and Richard D. Jones] have increased localized the functional domains to specific re- the value of the bequest considerably-from -$8 ceptor-, heparin-, and lipid-binding regions of million at the time of Mr. Gladstone's death in the proteins; characterized mutations in human 1971 to -$147 million today-and made possi- apo-E that cause type III hyperlipoproteinemia; ble the realization of Mr. Gladstone's dream of and discovered and characterized a genetic benefiting humankind through medical re- lipoprotein disorder, termed familial defective search. From an initial complement of 25 em- apo-B 100. ployees in 1979, the Institutes have grown to a Gladstone researchers have been particularly total staff of 225, including 18 faculty-level sci- successful in the production and study of trans- entists, fellows, students, volunteers, and re- genic mice and rabbits expressing a variety of search and administrative support personnel. In genes important in cardiovascular disease, in- 1997, the combined research budget for the In- cluding those for apo-E, apo-B, acyl CoA:choles- stitutes was $20.5 million. terol acyltransferase, and a-tocopherol transfer The Gladstone Institute of Cardiovascular protein. Other research focuses on the modifica- Disease, established in 1979 with Robert W. tion and study of G protein-coupled receptors, Mahley, M.D., Ph.D., as its Director, has focused transfection of potentially therapeutic genes into on the causes, complications, and prevention of vascular cells, the molecular mechanisms of cy- atherosclerosis. Since its inception, the Institute tokine receptors, and mechanisms of apo-B has relied on a distinguished Advisory Board mRNA editing. whose members, including two Nobel laureates, The Institute also engages in several signifi- scrutinize the direction and progress of research. cant outreach efforts. The Lipid Disorders Train- The Institute occupies about 48,000 square feet ing Center educates physicians and other health of laboratory and office space and is organized care providers in the clinical management of plasma lipid disorders. The Gladstone Lipid Clinic Address correspondence and reprint requests to: Dr. Robert is a patient-care teaching program involving W. Mahley, The J. David Gladstone Institutes, Box 419100, UCSF medical school faculty, students, and pa- San Francisco, CA 94141-9100, U.S.A. Phone: 415-826- 7500; Fax: 415-285-5632; e-mail: tients. The ongoing Turkish Heart Study has pro- [email protected] duced fascinating data on a richly diverse and

Iid FIG. 1. (A) Gladstone Institute of Cardiovascular Disease and (B) Gladstone Institute of Virology and Immunology, San Francisco, California. little studied population with unique lipid char- advisory board is composed of internationally acteristics. recognized scientists, including one Nobel laure- In recent years, the discovery of apo-E4 as a ate. The Institute is divided into five units: the major risk factor for Alzheimer's disease (AD) Laboratory of Molecular Immunology, the Lab- prompted the Institute to expand its area of re- oratory of Receptor and Viral Signal Transduc- search into the neurosciences. The new Glad- tion, the Laboratory of Viral Pathogenesis, the stone Molecular Neurobiology Program, which Laboratory of Interleukin-2 Receptor Signaling, opened in 1996, pursues research into the mo- and the Antiviral Drug Research Division. lecular processes of AD, AIDS dementia complex, Research at the Institute focuses on basic and and other neurodegenerative diseases. Work has clinical research into HIV and AIDS. Current re- included studies of the role of apo-E isoforms in search projects include a broad range of strate- the pathogenesis of AD and the characterization gies in this effort. For example, experiments are of a transgenic rodent model that develops brain in progress to utilize the recent discovery of che- abnormalities similar to AD, including plaques mokine receptors as obligatory co-receptors for containing ,B-amyloid, a hallmark of the disease. viral cell entry to create small animal models of Other research concentrates on the role of in- HIV infection. Other work focuses on the mo- flammatory mediators (e.g., transforming growth lecular functions of the various HIV gene prod- factor ,31) and other injury-response factors in ucts, mechanisms underlying the perinatal neurodegeneration. transmission of HIV and the pathogenesis of The Gladstone Institute of Virology and Im- HIV in children and adults (particularly in the munology opened in 1993, the culmination of a organs of blood formation), strategies to en- cooperative effort by the State of California, the hance immune function in HIV-infected pa- City of San Francisco, UCSF, and the J. David tients (total lymph node irradiation), and the Gladstone Institutes. The California state legisla- effects of chemokine and cytokine signaling ture proposed the development of a basic health events in HIV infection. science center dedicated to unraveling the mys- The presence of the Gladstone Institute of teries of the AIDS virus and provided $12 million Virology and Immunology on the UCSF-affili- in building funds. In partnership, the J. David ated SFGH campus contributes to a critical mass Gladstone Institutes initially committed $28 mil- that promotes productive collaborations between lion and UCSF an additional $4 million to the AIDS researchers and the clinicians who direct research program. At the time, this commitment patient care in the internationally recognized constituted the largest contribution outside of UCSF AIDS program at SFGH. Gladstone scien- the NIH to biomedical research on AIDS. tists are involved in several efforts to speed the The Virology Institute, with 29,000 square development of new therapies from the bench to feet of state-of-the-art laboratories and offices, is the bedside. Through an agreement with the directed by Warner C. Greene, M.D., Ph.D., one NIH, the Institute's Antiviral Drug Research Di- of the country's leading molecular biologists. Its vision is using a mouse model of the human R. W. Mahley: Series: Molecular Medicine Institutions 571 immune system to evaluate compounds for po- force, bringing together scientists from many dis- tential use against HIV. The General Clinical Re- ciplines to share in scientific discussions, semi- search Center, established by the NIH at SFGH, nars, and other collegial opportunities. The ex- provides a means of further evaluating promising citing scientific environment of the Institutes also drug candidates in initial human trials. fosters a comprehensive and well-rounded bio- The J. David Gladstone Institutes are major medical training experience for its postdoctoral contributors to the basic and clinical research fellows and graduate students. The future offers and training endeavors of UCSF and SFGH. Their exciting challenges for the Institutes as new areas presence on the SFGH campus acts as a cohesive of research interest are added.