Brian Nelson Griffith, Ph.D. Associate Professor of Biomedical Science Teaching: Biochemistry and Nutrition Mentor: Lisa M. Salati, Ph.D.
Office: A-314 Phone: (304) 647-6225 Fax: (304) 645-4859 Cell Phone: 304-661-4993
Ph.D from West Virginia University School of Medicine
M.S. from West Virginia University; Morgantown, WV
B.S. in biology and B.A. in chemistry from Alderson-Broaddus College; Philippi, WV
The overall goal of our current research project is to identify new pharmacological and nutrition therapies for the prevention of myocardial infarction induced cell death.
An osteopathic physician's first and last duty in patient care according to Dr. Andrew Taylor Still is to "look well to a healthy blood-and-nerve supply." The ability of the heart to maintain healthy blood and aerobic metabolism is important for maintaining cellular homeostasis as well as cardiac structure and function. Therefore, when a person experiences a myocardial infarction (MI), reestablishing blood flow to the ischemic area is essential in order to preserve cardiac structure and function.
Reperfusion therapy, caused by restoring blood flow to the ischemic area, can ironically cause myocardial cell death by activating cell apoptosis and/or cell necrosis. Thus, reperfusion therapy can cause structural damage to the heart, alternations in cardiac function, the development of heart failure and ultimately death. Therefore our laboratory is interested in investigating new pharmacological and nutritional therapies to prevent post-MI-induced-IR injury caused by reperfusion therapy. Thus, our ultimate goal is to restore cellular homeostasis following IR-injury.
The study described above is funded by a WVSOM intramural grant.
One consequence of IR injury in the heart is oxidative stress with the subsequent depletion of NAD+ levels. We have previously shown that niacin (Vitamin B3), a precursor for NAD+, reduces IR-induced apoptosis. The question of how NAD+ depletion contributes to IR-injury is unknown but may involve SIRT1, a type III, NAD-dependent histone deacetylase (HDAC) and one of its downstream targets, the transcription factor NFκB. Therefore, we plan to explore the role of SIRT1 and NFκB in IR injury.
Resveratrol, a compound found in red wine, is known to have anti-aging, anti-oxidant, and more importantly, cardioprotective effects. It has been shown to work via several downstream targets including SIRT1. However, the involvement of SIRT1 in the cardioprotective effect of resveratrol is still not understood. Therefore, we explored the effect of both resveratrol and the selective SIRT1 activators, DCHC and Cay10591, on IR injury in HL-1 cells. Our initial studies demonstrate that both DCHC and Cay10591 reduce IR-induced caspase-3 activity, a biomarker of cellular apoptosis.
Other targets being explored in our laboratory include NFκB, a master controller of inflammatory cytokine and chemokine production. Recently, it was shown that SIRT1 activity in adipose tissue controls NFκB activity, as demonstrated by siRNA knockout animals and transgenic knockout animals. Therefore, since inflammation plays a major role in IR injury and progression to heart failure, we propose to explore the connection between SIRT1 activity, NFκB transcriptional activity, and IR injury in cardiac myocytes.
Our laboratory uses a variety of molecular, histological, and biochemical approaches to study IR injury. To begin with we use an in vitro cell line referred to as HL-1 cardiac myocytes to study the effects of different agents on IR-injury. We also use flow cytometry which quantifies apoptotic and necrotic cell populations (see figure 2). And, lastly we use an in vivo mouse model of IR-injury. Basically, we occlude the left descending coronary artery (LAD) of a mouse heart and then measure the infarct size and collagen deposition through a series of histological stains. In addition, we also use echocardiography to measure cardiac parameters. It is our goal to find a pharmacological or nutrition agent which reduces IR-injury in both an in vivo and in vitro model.
An interesting project in our laboratory involves aging. Most myocardial infarctions typically occur in older human patients; however most of the research involving mouse models use young animals. Thus we are interested in exploring the effects of aging on cardiac parameters in an attempt to study the effects of IR-injury in young versus old animals. It is our hypothesis that older animals will show a more profound effect of IR-injury as opposed to younger animals.
Our research team includes Dr. Judith Maloney, a collaborator from Marquette University, Bethany Hampton, Millie Mattox and multiple WVSOM students.
As a public health research project, we are interested in evaluating the disparity between self-perceived health and health status and behaviors in rural Appalachia.
The area of rural Appalachia was demarcated in 1965 by the Appalachian Regional Commission. This area consists of 365 counties in 12 states and all 55 counties of West Virginia. The Appalachia region is one of the unhealthiest regions in the United States. Our research was the first to show a disparity between self-perceived health and health status and behaviors within rural Appalachia.
It is our goal to improve the health status of rural Appalachians, by stimulating a change in the public health message and health programs targeted at rural Appalachians.
Dr. Wayne Miller.
This research is supported by the West Virginia School of Osteopathic Medicine.