Health and Human Development funds biological mechanisms research

Mechanisms of neurovascular dysfunction in humans with psoriasis

Principal Investigator: Lacy Alexander, research associate professor of kinesiology

Investigators: Sara Ferguson, assistant professor of dermatology

Abstract

Mechanisms of Neurovascular Dysfunction in Humans with Psoriasis
Psoriasis is a chronic inflammatory disease that affects approximately 2-4% of the population. While it is commonly known as an itchy disfiguring skin disease, it is also independent risk factor for cardiovascular disease, because atherosclerotic cardiovascular disease (ASCVD) and psoriasis share common underlying inflammatory causes. Evidence from large epidemiological studies strongly supports this connection, but the underlying common inflammatory causes producing the increase in ASCVD risk in psoriasis patients have not been thoroughly investigated. Additionally, it is unclear whether common treatments for psoriasis including drugs like Humira™ (injectable inflammatory-inhibitors) may reduce ASCVD risk.  Two measureable outcomes associated with increased cardiovascular disease risk include heightened activity of the sympathetic nervous system and dysfunction of the small blood vessels throughout the body. Heightened sympathetic nervous system activity is evident in adults with psoriasis when assessed using indirect measures and is coupled to alterations in how the blood vessels are control. However, to date, no studies have directly measured sympathetic nerve activity (SNA) in this patient population utilizing a specialized technique called microneurography, nor have the underlying causes of blood vessel dysfunction been studied. Understanding the causes contributing to impaired sympathetic nervous system and blood vessel control in psoriasis and the effectiveness of commonly used psoriasis treatments has the potential to shift how psoriasis is treated clinically. With the focus shifting to controlling the skin lesions while preventing cardiovascular complications.

The effects of route of administration of contraceptive hormonal therapy on hepatic production of IGF-1 and bone metabolism

Principal Investigator: Mary Jane De Souza, professor of kinesiology and physiology

Investigators: Madhusmita Misra, associate professor of pediatrics (Harvard University); Nancy Williams, professor of kinesiology and physiology; Richard Legro, obstetrics and gynecology; David, Wagstaff, research technologist, Methodology Center; Rebecca Mallinson, project coordinator; Karsten Koehler project coordinator

Abstract

Despite widespread use of oral contraceptive therapy, investigators to date have failed to definitively answer a basic question: Is oral contraceptive therapy helpful or harmful to bone health in the 18 million women who use them? Given the large number of women who use these drugs, it is alarming that we still do not know the answer to this basic question. For physically-active women, oral contraceptive use may pose a unique threat as findings suggest that oral contraceptives, in combination with exercise, may be particularly detrimental to bone. The reason (mechanism) for the harmful effects of oral contraceptive use on bone likely involves the “processing” of orally-administered hormones by the liver, a phenomenon referred to as the “first pass effect”. This “first pass effect” likely suppresses the liver production of an important hormone necessary for bone formation, known as insulin-like growth factor-1 (IGF-1). However, the consequences of the “first pass effect” of oral contraceptives may be avoided or minimized by alternative routes of administration that circumvent the liver. Indeed, transdermal contraceptives, which are administered as a skin patch and vaginal contraceptives, which are inserted into the vagina, may offer a good alternative to oral therapy because these alternate routes of administration may not suppress the liver release of IGF-1 and markers of bone formation that are essential for bone health. The purpose of this study is to examine the effects of the route of administration of contraceptive therapy on liver production of IGF-1 and markers of bone metabolism. This study will determine whether the negative effects of oral contraceptives on liver IGF-1 production and bone formation reflect the route of administration such that an attenuation of these effects is observed when non-oral therapy is tested. The proposed project will address the consequences of the “first pass effect” of oral vs non-oral (transdermal and vaginal) contraceptives on the liver production of IGF-1 and markers of bone formation. We will assess mechanistic effects by way of two-day serial sampling and by a test of how the liver is producing IGF-1, called an IGF-1 Generation Test, before and after 2 months of oral, transdermal or vaginal contraceptive therapy. This study will be the first to examine the mechanisms whereby oral contraceptives affects bone health in the millions of women who use them.

Reproductive physiology maternal vitamin d deficiency, implantation and placental development in mice: the stage is set before the play begins

Principal Investigator: Alison Gernand, assistant professor of nutrition

Investigators: Francisco Diaz, associate professor of reproductive biology; Margherita Cantorna, Distinguished Professor of Molecular Immunology; Troy Ott, professor of reproductive biology

Abstract

Mothers around the world are deficient in vitamin D, which has been linked to numerous poor pregnancy outcomes including poor growth of the fetus, preterm birth, and preeclampsia. There are few studies that have tested vitamin D supplementation in pregnancy and most have started late in pregnancy. These studies have shown that vitamin D levels improve, but no other consistent benefits were found. Perhaps the late start of supplementation, after the placenta has formed, is the reason supplements have failed to improve pregnancy outcomes. We propose that lack of vitamin D in the mother before and during the earliest stages of pregnancy will impair normal formation and development of the placenta, leading to higher pregnancy loss and impaired growth and function of the placenta. This study will determine the effects of vitamin D status before and during pregnancy on the placenta in mice, a difficult to impossible task in humans. We will create a sufficient vitamin D status group with diet and deficient vitamin D status group using a genetic knockout mouse. The diets will be fed from the time the mice are in adolescence through getting pregnant and early pregnancy. We will examine mice at 6.5 days and 12.5 days of pregnancy. Implantation and placental development are similar in humans and mice, allowing this study to inform other critical work in humans. Ultimately, this work will allow understanding of the effects of low vitamin D in the earliest stages of pregnancy on placental growth and function. This study capitalizes on the extensive expertise at Penn State in the areas of reproduction and vitamin D research and benefits from the collaboration of highly accomplished investigators with existing laboratory capacity to achieve these aims within one year. These results will inform future human trials by the Principal Investigator, to better understand when vitamin D supplementation in women is needed, with the potential to reduce illness and death rates with a simple, feasible public health intervention.

The influence of nicotinic acetylcholine receptors in adolescent alcohol behaviors

Principal Investigator: Helen Kamens, assistant professor of biobehavioral health

Investigator: Laura Klein, professor of biobehavioral health

Abstract

Alcohol is a commonly used substance that can lead to addiction and other negative health consequences.  Individuals who drink more alcohol as adolescents are more likely to consume large amounts of alcohol as adults. This project examines the role of nicotinic acetylcholine receptors in adolescent alcohol behaviors. These receptors have been implicated in behaviors associated with alcohol use in adult animals, but there is limited knowledge of their involvement in adolescent alcohol behaviors. This project will take multiple approaches to understand the role that these receptors play in adolescent alcohol behaviors. The proposed project will increase our knowledge by providing a better understanding of the biological contributions to adolescent alcohol use and may be informative for the development of treatment strategies.

Inflammatory mechanisms of cardiac cell death in the aged female rat heart

Principal Investigator: Donna Korzick, professor of physiology and kinesiology

Abstract

Heart disease remains the leading cause of death in older women and may be associated with chronic inflammation. Menopausal loss of estrogen and increased cardiovascular disease risk may also be linked to an increased mitochondrial calcium sensitivity leading to increased incidence of cell death following ischemia/reperfusion injury which is exacerbated by chronic inflammation. By studying linkages between chronic inflammation, age-associated loss of estrogen, mitochondrial function, and markers of programmed necrosis, apoptosis, and autophagy within a true model of aging and menopause, new therapies for the treatment and prevention of heart disease in post-menopausal women may be realized.

Role of lipocalin 2, an innate immune protein in catalytic iron holmeostatis

Principal Investigator: M. Vijay Kumar, assistant professor of nutrition

Investigators: Matthew Fantle, associate professor of geosciences; Thomas Spratt, associate professor of biochemistry

Abstract

Iron is one of the most abundant metals on Earth and is vital to all living organisms and to human health. Iron deficiency can result in number of health complications such as fatigue, poor work performance, and decreased immunity. On the other hand, excessive amounts of iron can result in toxicity and even death. In humans, several health disorders can lead to iron-overload and also associated with dietary habits. Additionally, people that are on frequent iron supplementation and blood transfusions are at higher risk of iron overload, which can lead to liver and heart complications. Furthermore, the steady increase in the use of iron-derived particles in medical diagnosis poses an increased risk of iron toxicity. Oral or dietary iron supplementation used to treat anemia can also aggravate intestinal diseases by favoring intestinal bacterial overgrowth. In addition, iron is linked to number of diseases including obesity, diabetes, and heart disease. Therefore, the body possesses several proteins to finely regulate iron levels. One such protein recently identified is Lipocalin 2. This protein’s levels increase several log orders in a plethora of inflammatory diseases and may help to control iron levels. However, the extent to which lipocalin 2 protect against iron toxicity, specifically during iron over-load and inflammation, is largely unknown. We will test this hypothesis in well-established mouse models of dietary and inflammation induced iron toxicity.

Mechanisms of altered circulatory control with age: Are men and women different?

Principal Investigator: David Proctor, professor of kinesiology and physiology

Investigators: James Pawelczyk, associate professor of kinesiology and physiology; Gail Thomas, professor of medicine

Abstract

Older adults are encouraged to exercise for maintenance of functional independent and cardiovascular-metabolic health.  However, older adults, and in particular older post-menopausal women, exhibit exaggerated increases in arterial blood pressure and smaller increase in muscle blood flow when the exercise.  Older women also have stiffer hearts, and smaller/stiffer conduit arteries than other groups.  Collectively, these cardiovascular alterations could negatively impact the safety of, and capacity for, exercise in older women.  The proposed seed grant will provide preliminary support for a larger NIH grant application designed to address the following questions (1) Is neural constrictor outflow directed toward blood vessels in the arm and leg muscles the same, higher, or lower in older (compared to younger) women and men when they exercise?  (2) Do older adults (either sex) show a greater amount of constriction in these blood vessels during exercise compared to their young counterparts?  (3) What are the consequences of any observed age group differences blood vessel responsiveness on the build-up of metabolites in the working muscles, and the work of the heart, during tasks simulating activities of daily living?

Effects of culinary spices on lipid metabolism, gut motility, and fat excretion: Evaluating a new dietary strategy for improving fat metabolism (and perhaps obesity)

Principal Investigator: Sheila West, professor of biobehavioral health

Investigators: Penny Kris-Etherton, Distinguished Professor of Nutrition; Josh Lambert, associate professor of Food Science; Greg Shearer, associate professor of nutrition; Matam Vijay Kumar, assistant professor of nutrition; Mosuk Chow, associate professor of statistics

Abstract

Over the last two decades, our laboratory and others have made great progress in identifying foods and dietary patterns that lower cardiovascular disease (CVD) risk factors. Unfortunately, translation of these findings for widespread usage is limited because many of the best validated foods (nuts, oils, chocolate, etc) are relatively expensive and also high in calories. As an alternative, our recent data suggests that commonly used, culinary spices are a powerful, low-calorie method for improving metabolism of high fat meals. Our lab has shown that meals containing a high antioxidant spice blend (containing black pepper, cinnamon, cloves, garlic, ginger, oregano, paprika, rosemary, and turmeric) reduces appearance of fat in the blood (triglycerides) by up to 30%. Further analysis showed that these same spices inhibit an enzyme involved in fat absorption. However, the mechanism through which the spice blend reduces the triglyceride response is unknown. We hypothesize that the mechanism for these positive outcomes is enhanced excretion of fat in the feces and slowed emptying of the stomach; if this is indeed the case, it will have important implications for prevention of obesity and CVD. Further development of this model will allow us to evaluate a range of doses and combinations of spices in order to identify the most effective combinations for improving fat metabolism and gut health.

The impact of calorie-restricted weight loss on food intake following acute exercise in overweight young women: Role of appetite regulating hormones and eating behavior phenotypes

Principal Investigator: Nancy Williams, professor of kinesiology and physiology

Investigators: Mary Jane De Souza, professor of kinesiology and physiology;
Karsten Koehler (project coordinator); Barbara Rolls, Helen A. Guthrie Chair and professor of nutrition

Abstract

Reducing the amount of calories in our diet (calorie restriction) helps to create an energy deficit, which in turn will lead to weight loss. Despite successful weight loss through calorie restriction, most people regain at least part of the weight they initially lost. Exercise can help to prevent this weight regain, and the reason for this effect may be that following a bout of exercise, most people eat fewer calories than they expended during the exercise. This suppression of food intake after exercise seems to be related to two factors. One is the changes in hormones that signal feeling hungry and satiated (appetite-regulating hormones) that occur during and after exercise, and the second is how well individuals are capable of controlling what and how much they eat (eating behavior). Thus far, the effect of exercise on food intake and the role these factors (appetite-regulating hormones and eating behavior) have only been studied in men and women with a stable body weight. It remains to be determined how weight loss through calorie restriction impacts what and how much people eat after exercise, particularly in overweight women. Weight loss through calorie restriction causes a strong drive to eat more food in order to restore energy balance. This drive to eat more could lessen the hormonal changes caused by exercise that suppress appetite and hunger and override a person’s control over their food intake. Consequently, exercise may not be as effective in suppressing food intake and preventing weight regain following calorie-restricted weight loss. The purpose of this study is to assess how weight loss achieved through caloric restriction affects food intake after exercise. For this purpose, overweight young women will be guided to lose weight through calorie restriction for 4 weeks. Before and after the weight loss, women will undergo an exercise test and will be asked to eat as much as desired (ad libitum) after the exercise, and their food intake will be recorded. We will further assess changes in appetite-regulating hormones and other aspects of eating behavior to determine how changes in these factors are related to changes in food intake. This study will expand our knowledge about how exercise can protect against weight regain. The study will further improve our knowledge about appetite regulating hormones and eating behavior and how both factors are related to food intake after exercising. The project has the potential to help improve future weight loss programs by helping us to understand the roles that both the underlying biology and the behavior of a person play in body weight regulation as it involves dieting and exercise.