Ryan A. Harris, Ph.D. - US grants

DESCRIPTION (provided by applicant): Cystic Fibrosis (CF) is the most common, deadly, genetic disease in North America and is diagnosed in approximately 1,200 individuals each year. Over 20 years ago, exercise intolerance was shown to predict mortality in patients with CF, independent of lung function. In addition, lower exercise capacity is associated with greater mortality, steeper decline in pulmonary function, and more pulmonary infections. A critical barrier to improving exercise tolerance in patients with CF is our lack of knowledge regarding the different physiological mechanisms which contribute to their lower exercise capacity. Clinical manifestations of CF not only include lung dysfunction, but many additional systemic consequences as well. In fact, our group has recently published the first evidence of systemic endothelial dysfunction in young patients with CF and now we have compelling preliminary data to support that patient's with CF exhibit an impairment in blood flow regulation during exercise. Accordingly, the overall goals of this proposal are to 1) provide proof of concept for using PDE5 inhibition to improve exercise capacity in patients with CF and 2) investigate blood flow per se and endothelial dysfunction as potential mechanisms that contribute to exercise intolerance in CF. Our central hypothesis is that PDE5 inhibition will improve blood flow (acute treatment) and endothelial function (chronic treatment) leading to an increase in exercise capacity. We are proposing a randomized, placebo controlled, acute experiment (aim 1) followed by an open label 4 week treatment trial (aim 2). Findings from aim 1 will isolate the transient increase in blood flow delivery as a mechanism to improve exercise capacity in CF, whereas findings from aim 2 will target an improvement in endothelial function and therefore, the improvement in exercise capacity will likely be greater in magnitude and sustainable The impact of this proof of concept investigation will test PDE5 inhibitors as a potential therapy in CF and will explore blood flow and endothelial function as potential mechanisms which contribute to exercise intolerance in CF. This proposal, through the integration of exercise physiology, vascular biology, and pharmacology, represents a major breakthrough in the approach to begin understanding the mechanisms which contribute to exercise intolerance in CF.

Diabetes has recently been referred to as ?the epidemic of the 21st century? and contributes to a substantial economic burden on the United States public health. Cardiovascular disease (CVD) accounts for 80% of morbidity and mortality in diabetes, however, women with type 1 diabetes have a substantially greater risk for CVD compared to men with diabetes. A critical barrier to understanding this sexual dimorphism in CVD risk is the lack of knowledge regarding the role of estrogen (E2) on vascular health in diabetic women. Oxidative stress is a common phenotype in patients with diabetes and is routinley associated with hyperglycemia and diabetic complications. In addition, sirtuin1 (Sirt1) has been proposed to play a fundemental role in regulating nitric oxide (NO) bioavailability, and is lower in patients with diabetes. Accordingly, our central hypothesis is that an elevated concentration of E2 in women with type 1 diabetes contributes to a reduction in NO- bioavailability and vascular health through two separate pathways; an increase in oxidative stress and a decrease in circulating Sirt1. In support, compelling preliminary data indicate that the natural increase in vascular health from menses to the late follicular phase of the menstrual cycle is lost in the presence of type 1 diabetes. In addition, this loss is associated with increased oxidative stress and lower Sirt1. To investigate the impact of E2 on vascular health in women with diabetes, we propose to utilize the menstrual cycle as a natural and novel method to investigate changes in sex-steroid hormones. We will perform a comprehensive assessment of vascular health in men and at two different times during the menstrual cycle in premenopausal women with and without type 1 diabetes: 1) during the menses (low estrogen/low progesterone) and 2) late follicular (elevated estrogen/low progesterone) phases. In addition, we will employ two novel treatments that may mitigate future CVD risk in patients with diabetes. Findings will not only contribute to understanding the molecular mechanisms associated with sex disparities of CVD risk in diabetes, they may identify novel therapeutic approaches to decrease estrogen-mediated vascular dysfunction in women with diabetes. This proposal demonstrates the true model of translational research and represents a major shift in the approach to understanding the sexual dimorphism of CVD risk in patients with type 1 diabetes.

Project Summary Population-based studies have traditionally focused on measurement of body fat (i.e. obesity) to assess the contribution of poor lifestyles to insulin resistance and cardiovascular risk. While much less recognized is the role of skeletal muscle in these conditions. Built on our proposed biobehavioral model which incorporates multi- dimensional evaluation of skeletal muscle health (i.e. mass, function, strength, and intermuscular fat infiltration) and its molecular transducer (i.e. myokine response to whole body vibration), the fundamental objective of this proposal is to evaluate the systemic contribution of skeletal muscle health in mediating the role of obesogenic lifestyles (i.e. psychosocial stress, unhealthy diet and physical inactivity) on insulin resistance and the development of preclinical markers of cardiovascular disease (CVD) (i.e. arterial stiffness, carotid intima media thickness and endothelial function). To evaluate the impact of environmental factors on manifestation of biological markers, genetic influences must be controlled. Building on our Georgia CV Twin Study which has evaluated a multi-ethnic twin samples of 532 twin pairs with roughly equal number of African Americans (AA) and European Americans (EA) 4 times over 15 years and has physical activity and psychosocial stress collected during these visits, we will conduct one additional follow-up visit (age range 22-45 yrs) to measure skeletal muscle health, insulin resistance and preclinical markers of CVD. The specific aims are to test the hypotheses that: (1) Obesogenic lifestyle factors (i.e. psychosocial stress, physical inactivity and unhealthy diet) will jointly or distinctively impair skeletal muscle health, and impaired skeletal muscle health will be the pathway through which obesogenic lifestyle factors exert their influence on insulin resistance and preclinical markers of CVD. (2) Myokine response to whole body vibration will be the molecular transducers mediating the effect of skeletal muscle health on insulin resistance and preclinical markers of CVD. (3) Ethnicity and gender may modify the influence of obesogenic lifestyle factors upon aim 1 and 2. The secondary aims are: (1) To examine whether skeletal muscle health can explain the health disparity between AAs and EAs in the risk of type 2 diabetes and CVD. (2) To examine the potential effects of gene-environment interactions on skeletal muscle response to obesogenic lifestyles. This proposal represents a paradigm shift by focusing on impairments in skeletal muscle rather than adiposity as a cause of poor lifestyle induced metabolic and vascular dysfunction. This information can not only guide the effective dissemination of the knowledge and increase the success rate of behavior changes, but also has the potential to generate new treatment strategies targeting the critical illness in which skeletal muscle as a determinant of survival. Furthermore, increased understanding of the mechanisms contributing to health disparities between AAs and EAs will enable the development of ethnicity- specific prevention strategies.