Current Projects

Current Phase II Project Leaders

Project Summary: Aging is the primary risk factor for Alzheimer’s disease (AD) which is the most common form of dementia and among the fastest growing causes of morbidity and mortality in the United States. The risk factors for AD emerge during midlife and are similar to cardiovascular and cerebrovascular diseases. In this regard, stiffening of the large elastic arteries (i.e., the aorta and carotid arteries) and cerebral hypoperfusion occur with aging and are linked to age-related cognitive impairment, primarily through the transmission of damaging pressure waves to the cerebral vasculature, resulting in cerebrovascular dysfunction and neuronal damage. The impact of midlife vascular changes on the brain are further exacerbated by poor lifestyle habits, including the consumption of a diet that contains high amounts of added sugar (e.g., from ultra-processed foods containing high amounts of fructose). While the exact mechanisms are not known, a high sugar diet is associated with elevated plasma triglycerides (TGs), which may exacerbate age-related arterial dysfunction and memory impairment through a mechanism involving increased systemic inflammation. Our cross-sectional preliminary data suggest that plasma TGs are strongly associated with increased arterial stiffness, reduced cerebrovascular function, lower memory scores and decreased integrity of the hippocampus, a brain structure that is critical for encoding and recalling memories; however, it remains unknown how these factors are influenced by the consumption of added sugars. The purpose of this project is to establish preliminary evidence for a causal link between added sugar intake and adverse changes to vascular and brain health in midlife adults. Our central hypothesis is that excess added sugar intake causes reductions and hippocampal structure and function though adverse changes to arteries via a mechanism involving increased plasma TGs and systemic inflammation. We will conduct a randomized, single-blind, controlled-feeding study to determine the effects of consuming a diet containing low (5% of total energy intake) vs. high (25% of total energy intake) added sugar for 10-days each on measures of large elastic artery stiffness, cerebrovascular function and hippocampal structure and function. The expected outcome is evidence of a causal relation between added sugar intake and reductions in vascular and brain functions through a mechanism involving increased TG’s and inflammation. The data generated from this project will support a future NIH R01 proposal for a randomized controlled trial aimed at lowering added sugar intake in mid-life adults.

Project Summary: Dementia is a debilitating syndrome with many incapacitating symptoms requiring dependent care that is emotionally and financially burdensome for patients and their families. Dementia is the 6th leading cause of death in the United States with 47.5 million people worldwide currently living with dementia which is projected to reach 75.6 million by 2030 and 135.5 million by 2050. Unfortunately, no therapies to treat dementia exist, indicating a critical and urgent need for a better understanding of how dementia is initiated and progresses so that new therapeutic approaches can be developed. Age-related stiffening of the large elastic arteries is a major contributor to dementia but the mechanism(s) by which this occurs remain unknown. In healthy individuals, pulsatile flow in large vessels is converted to continuous flow in cerebral µvasculature via pulsatility dampening by large arteries. Repeated cycles of distension and relaxation over time induce irreversible elastin fragmentation in large arteries which is replaced by stiffer collagen thereby diminishing compliance and dampening. This results in the conversion from continuous to pulsatile flow in cerebral microvasculature accompanied by increases in pulse pressure and pulse wave velocity. These pathological hemodynamics have been linked to cognitive decline via neuronal injury, synaptic dysfunction, and neurodegeneration. While most hypotheses focus on shear- induced injury mechanisms, endothelial cells and neurons are also sensitive to strain. We hypothesize that induction of cyclic strain, in the microvessel wall and adjacent tissue, due to the conversion to pulsatile flow, exacerbates shear-induced brain microvascular endothelial cell (BMEC) dysfunction and is the primary cause of neuronal injury. We will test our hypotheses via fulfillment of two aims. (1) Investigate the independent, and combined influences of, conversion to, and increases in, cyclic shear stress and cyclic strain on BMEC dysfunction and inflammation. We hypothesize that conversion from continuous to pulsatile flow, and an increase in pulse wave velocity, induce BMEC dysfunction and inflammation via exposure to increased cyclic shear stress. We further hypothesize that cyclic strain in the microvascular wall, and increase in strain magnitude due to increased pulse pressure, exacerbate shear-induced BMEC dysfunction. (2) Investigate the influence of cyclic strain on neuronal injury. We hypothesize that as pulse pressure increases, the associated increase in strain will induce neuronal injury via strain propagation into tissue and neurons adjacent to the vessel and that this process worsens with age-related brain softening. The results of this proposal will provide significant insight into how pathological hemodynamics induced by arterial stiffening lead to BMEC and neuronal injury.

Title: Family Meals as a strategy for the primary prevention of cardiovascular disease in children.

Project Summary: Cardiovascular disease (CVD) is a leading cause of death in the United States (US). Data from the famous Bogalusa Heart Study have demonstrated the pathogenesis of CVD can start in young children, with early manifestation directly associated with obesity. Inter-related with obesity, is poor diet quality, and poor diet quality has been identified as a leading cause of CVD. The long-term goal of this work is to identify strategies that can be easily implemented by families for the primary prevention of CVD in children. The home feeding environment, where parents serve as the gatekeepers of the foods available to children has been identified as a key influence on eating behavior. Within the home feeding environment observational work has demonstrated more frequent family meals is associated with increased dietary quality, greater consumption of fruits and vegetables, decreased risk for overweight and obesity, and positive psychosocial outcomes. Family meals may serve as a vehicle to promote the prevention of obesity and promote CVD health in young children, but the rigor of prior research has not sufficiently tested family meal frequency as an intervention target. The objective of the proposed randomized controlled trial is to examine the efficacy of family meal frequency as an intervention target in addressing the primary prevention of CVD. Ninety children (6-12 years-old) and their parent will be randomized to one of two interventions: (1) increasing family meal frequency, or (2) increasing fruit and vegetable intake. Both intervention arms will receive a prevention-focused family-based multicomponent lifestyle modification program, the gold standard in behavioral-based intervention research. CVD risk factors of interest include diet quality (Aim 1), zBMI (Aim 2) and cardiovascular health as assessed by blood pressure, fasting blood insulin, blood lipids, vascular function (Aim 3). Given, the family-based nature of the study the moderation of parent change over time will be examined as an exploratory aim. The comprehensive evaluation of CVD risk factors will be used to elucidate the relationship with family meal frequency, a proposed vehicle within the home feeding environment for the primary prevention of CVD in children.

Title: Obesity-induced endothelial dysfunction in arteries of visceral adipose

Project Summary: Obesity is an overwhelming epidemic and healthcare burden. The cardiovascular risk associated with obesity is well-documented, yet specific pathophysiological mechanisms are poorly understood. The broad, long term objective of this application is to define mechanisms driving obesity-induced cardiovascular dysfunction. Obesity causes endothelial dysfunction in visceral adipose arteries (VAA) whereas subcutaneous adipose arteries (SAA) remain functional. This dichotomy in vascular function presents a unique opportunity to identify novel, vascular bed-specific targets in combatting cardiovascular disease in obesity. A hallmark of endothelial dysfunction is reduced dilations to increased blood flow. We recently identified flow- activated Kir2.1 channels as critical regulators of flow-induced vasodilation. Furthermore, our preliminary evidence reveals that reduced dilations to flow in VAA of obese mice and humans is through inhibition of endothelial Kir2.1, whereas SAA Kir2.1 function is intact. This implicates Kir2.1 as a novel, vascular bed-specific target. The goal of the present study is to determine the mechanisms of obesity-induced endothelial dysfunction that result in the loss of Kir function specifically in VAA. We show that Kir2.1 inhibition is dependent on the presence of CD36, a scavenger receptor that is upregulated in obesity. CD36 contributes to the cellular uptake of fatty acids, derivatives of which are well-known to inhibit Kir2.1. We will determine the role of CD36 in inhibiting Kir2.1 in VAA of obese mice and humans. Our hypothesis is that elevated CD36 results in increased fatty acid uptake into endothelial cells which leads to the inhibition of Kir2.1 and endothelial dysfunction. We propose that the underlying impairment of VAA lies in the obesity-induced increase in the expression and function of CD36 in mice and humans and results in Kir2.1 inhibition in VAA, effects that do not occur in SAA with obesity. The proposed studies, as part of the NIH COBRE Phase 2, will provide the foundation for the applicant’s procurement of an NIH R01. The major project milestone is to produce adequate preliminary data by the completion of this project to support a competitive R01 proposal. The main career goal of the applicant is to establish a successful, externally funded research program using gold standard approaches to identify new targets in cardiovascular disease. The University of Delaware provides a resource rich environment befitting of a productive research position.

Current Phase II Pilot Project Awardees

Previous Phase II Pilot Project Awardees