August 31, 2001

Inagami receives MERIT award after lengthy career

Featured Image

Inagami receives MERIT award after lengthy career

Tadashi Inagami, Ph.D., Stanford Moore Professor of Biochemistry, thought he was getting close to retirement.

That was before the National Institutes of Health opted not only to fund his most recent grant, but also convert it to a MERIT award. The MERIT – Method to Extend Research in Time – award provides up to 10 years of continuous funding, without competitive review.

So Inagami will forego retirement’s golf games and instead continue his career-long search for the molecular culprits involved in hypertension, heart failure, and vascular diseases. It is a search that has already yielded valuable drug targets for the treatment of these diseases.

In his 35 years at Vanderbilt, Inagami has unraveled secrets of cardiovascular regulation by the renin-angiotensin system. Renin is an enzyme released into the blood by the kidneys. Its presence in the blood launches a chain of reactions that result in the production of angiotensin II, a molecule that raises blood pressure.

Inagami and colleagues were the first to isolate pure renin, a protein that had been described 70 years earlier but had eluded purification. The research environment at Vanderbilt in the 1960s prompted his discovery, Inagami said. He was working with Stanley Cohen, Ph.D., Distinguished Professor of Biochemistry, Emeritus and Nobel laureate, to characterize epidermal growth factor (EGF) when Cohen suggested that Inagami attempt to isolate renin from mouse salivary glands – the same tissue used by Cohen to isolate EGF.

“It was good fortune,” Inagami said of the research that laid the foundation for subsequent studies of the renin-angiotensin system.

At about the same time, pharmaceutical companies were developing the ACE inhibitors, drugs that proved to be very effective in lowering blood pressure. Interestingly, Inagami said, these drugs worked not only for patients whose high blood pressure involved an elevated renin-angiotensin system, but also for patients with essential hypertension-high blood pressure resulting from unknown causes.

“This led investigators to the notion that the renin-angiotensin system is involved in many more types of hypertension,” he said.

Inagami and others thought that drugs directed at the receptors for angiotensin II-a peptide that raises blood pressure-might be even more effective anti-hypertensives than the ACE inhibitors. His laboratory cloned several angiotensin II receptors, which have been used by some pharmaceutical companies to develop new drugs that block these receptors and lower blood pressure.

In addition to its role in raising blood pressure, angiotensin II promotes the overgrowth of cells, called hypertrophy, in the heart and blood vessel walls and in the kidneys. The hypertrophic response to angiotensin II is a major problem, Inagami said, leading to heart failure, atherosclerosis, and kidney failure. With the MERIT award, he and colleagues will focus on the mechanisms underlying this cell growth response.

Inagami and Dr. Satoru Eguchi, research associate professor of Biochemistry, recently discovered that angiotensin II transmits growth signals through the pathways used by the EGF receptor. “It’s funny. I feel like I’ve come back to where I started,” mused Inagami, whose early work at Vanderbilt with Cohen involved EGF.

He and colleagues will characterize the molecules that link angiotensin II and EGF receptor signaling. “The mechanism for this is different than the blood pressure regulation,” he said. “It seems to be a second function of angiotensin II.”

Inagami believes that characterizing this cell growth-promoting function of angiotensin II will provide more targets for the treatment of cardiovascular diseases.

Other VUMC faculty members currently funded with MERIT awards are: Albert H. Beth, Ph.D., professor of Molecular Physiology & Biophysics; Alan D. Cherrington, Ph.D., Charles H. Best Professor of Diabetes Research, professor and chair of Molecular Physiology & Biophysics; Dr. Daryl K. Granner, Joe C. Davis Professor of Biomedical Science and director of the Vanderbilt Diabetes Center; David M. Lovinger, Ph.D., professor of Molecular Physiology & Biophysics; Dr. L. Jackson Roberts II, professor of Pharmacology and Medicine; Elaine Sanders-Bush, Ph.D., professor of Pharmacology and Psychiatry; Conrad Wagner, Ph.D., professor of Biochemistry; and Michael R. Waterman, Ph.D., Natalie Overall Warren Professor of Biochemistry and chair of the department.