LLU&MC Scope Autumn 2000

$7 million grant awarded for perinatal biology research project

The National Institutes of Health announced recently the award of a major grant to faculty members in the Center for Perinatal Biology, departments of physiolgy and pharmacology, School of Medicine. The award of $7 million over five years is for a project titled "Fetal and adult adaptations to long-term hypoxemia."

Perinatal biology researchers at Loma Linda take a moment to celebrate a five-year, $7 million grant from the National Institutes of Health. Shown, from left, are Charles A. Ducsay, PhD, professor of physiology; Raymond D. Gilbert, PhD, professor of physiology; Lawrence D. Longo, MD, distinguished professor of physiology, and professor of obstetrics and gynecology; John N. Buchholz, PhD, associate professor of pharmacology; William J. Pearce, PhD, professor of physiology; and Lubo Zhang, PhD, associate professor of pharmacology.

"This is fundamental, basic research that has been in progress since 1988 and is the only such study in the world," says Lawrence D. Longo, MD, distinguished professor of physiology, and professor of obstetrics and gynecology. "This new grant has engendered interest from scientists from Europe to South America and to Australia who wish to collaborate with us in this study."

The overall theme of this study is to explore the fundamental mechanisms whereby the fetus and adult adapt to long-term, high-altitude hypoxia. In addition, the studies examine several fundamental mechanisms in association with development of the fetus into an adult. This is a broadly based, multidisciplinary research program using physiologic, pharmacologic, biochemical, and molecular approaches to explore adaptations of the cardiovascular system, the cerebral blood vessels, uterine vessels, the fetal hypothalamic-pituitary-adrenal axis, and the myometrium in response to long-term hypoxia.

Studies are conducted in fetal and adult sheep acclimatized to high altitude (3,820 meters/12,470 feet), and in normoxic sea-level controls. They are based on 12 years of research by the LLU group at the White Mountain Research Station on the responses and acclimatization to high altitude.

The studies examine a number of hypotheses regarding physiologic, biochemical, and molecular mechanisms.

In the heart, for example, studies test hypotheses regarding the roles of calcium channels, Ca2+-induced Ca2+ release, beta receptor coupling to protein kinase A, and troponin and myosin ATPase isoforms in the response to long-term hypoxia. In the cerebral arteries, studies test hypotheses regarding alpha adrenergic receptor subtypes, their coupling to second messengers, the relation to intracellular calcium modulation by protein kinase C, the role of plasma membrane Ca2+ and K+ channels, vascular innervation, norepinephrine release and reuptake, relaxation mechanisms, etc., to long-term hypoxia. In uterine arteries, the research studies test several hypotheses regarding the mechanisms of modulation by cortisol, and how these mechanisms are altered by long-term hypoxia.

Finally, the studies also test several hypotheses regarding fetal hypothalamic-pituitary-adrenal responses to hypoxia, e.g., the role of adrenal adenylate cyclase and glucocorticoid receptors, as well as signal transduction mechanisms in the uterine smooth muscle.

From a scientific standpoint, these studies will further understanding of how the fetus and adult successfully adapt to chronic hypoxia. In addition, they will shed light on a number of aspects in the development from fetus to adult. From a clinical standpoint, these studies relate to the problems of prolonged hypoxia and successful high altitude acclimatization.

For the fetus and newborn they also relate to responses to prolonged hypoxia as occurs in women who live at high altitude, those who smoke or are exposed to environmental pollution, as well as those who are anemic, or who have heart or lung disease or with "placental insufficiency." For the newborn infant these studies relate to problems such as pulmonary hypertension, persistent fetal circulation, altered cerebrovascular function, and intracerebral hemorrhage. Finally, the studies give promise of shedding light on the mechanisms of the Barker hypotheses of prenatal programming of adult disease.

Headed by Dr. Longo, investigators include John N. Buchholz, PhD, associate professor of pharmacology; Charles A. Ducsay, PhD, professor of physiology; Raymond D. Gilbert, PhD, professor of physiology; William J. Pearce, PhD, professor of physiology; and Lubo Zhang, PhD, associate professor of pharmacology, with collaboration by J. Mailen Kootsey, PhD, professor of physiology, and eight investigators from other universities.

[Scope, Autumn 2000]