Duchenne Muscular Dystrophy (DMD) is a severe muscle wasting disease caused by the deficiency of dystrophin protein affecting ~1 in 3500 boys. Exercise has been investigated as a potential therapy but has shown conflicting effects on dystrophic muscle. Animal models that have been studied but do not fully mimic the disease and cardiac phenotype. Here, we provide the first known evaluation of exercise in a new DMD mdx rat model that mimics skeletal muscle and cardiac pathology. Having an animal model that better reflects the DMD cardiac phenotype is crucial in establishing physical activity guidelines that minimize potential damage to the heart. In Aim I of this pilot study, DMD mdx rats (n=3) and sibling wildtypes (WT; n=3) were assigned to wheel or treadmill exercise training groups (high intensity or low intensity) or unexercised (sedentary) for 6-weeks. Throughout this 6-week period, I was responsible for executing the rat treadmill exercise training protocol at low-to-moderate intensity (5x/week), and monitored the rat wheel running activity. Physiological measurements were conducted pre- and post- training (wheel running, treadmill testing, grip testing, echocardiography, and hindlimb force testing). Compared to wheel running or unexercised rats, treadmill training produced the greatest gain in treadmill exercise endurance testing and in fatigue-resistance in in-vivo hindlimb force testing for DMD rats. However, the treadmill program was associated with severe cardiac effects in DMD mdx, indicated by significant fibrosis and inflammation and echocardiography (Myocardial Performance Index, % fractional shortening and ejection fraction), a finding which will be investigated in subsequent cohorts.

The blood-brain barrier (BBB) is a highly specialized interface of brain microvascular endothelial cells (BECs). The main functions of BECs are to protect the brain against exposure to harmful substances in the blood, and to transport and secrete nutrients and other molecules that support normal brain functions. BECs can also alter their functions in response to signals from the brain or blood compartments. GLUT-1 is the predominant transporter at the BBB that regulates glucose entry into the brain, and does so by a mechanism of facilitated diffusion, which permits glucose transport in the blood-to brain or brain-to-blood direction. GLUT-1 dysfunction occurs in and may contribute to Alzheimer’s disease.The main hypothesis is that GLUT-1 malfunction in the BBB occurs as it deteriorates with age, which causes errors in other regulation methods of the BBB leading to the development of Alzheimer's. However, it is difficult to study mechanisms of GLUT-1 dysfunction at the BBB specifically because of the involvement of multiple cell types that regulate glucose uptake into the brain in vivo. In my research, I have utilized a model of iPSC-derived brain endothelial cells (iBECs) in order to study aspects of GLUT-1 regulation in an in vitro model of the BBB. Currently, my main findings have shown that the GLUT1 transporter is functional in our system, and that GLUT1 protein expression is increased and glycolytic enzymes are decreased when iBECs switch from a proliferative state to a quiescent state. Glucose transport in the blood-to-brain direction is decreased in the quiescent state.  Additionally, high glucose exposure causes downregulation of glucose transport.  My future studies aim to determine whether proliferating vs. quiescent iBECs respond differently to high or low concentrations of glucose. In summary, we have shown that iBECs are a translatable and effective model that allows us to further investigate the regulation of GLUT-1 at the BBB to further understand the physiological mechanisms involved in Alzheimer's Disease. 

Chronic non-bacterial osteomyelitis (CNO) is a rare disease where the immune system attacks healthy bone, leading to inflammation and destruction. Currently, the use of inflammation markers - which consists of a blood test for erythrocyte sedimentation rate (ESR) and c reactive protein (CRP), a clinical visit, and magnetic resonance imaging (MRI) are used to monitor the state of CNO. However, the reports from these assessments are inconsistent as longitudinal data allowing for a detailed analysis is lacking.Thus, we aim to investigate the association among these disease monitoring modalities using Seattle Children's Hospital CNO research database. The database which contains patients under 21 years old, spanning from January 2014 - January 2021 is one of the largest composed. We hypothesize that an increased presence of lesions, as observed through MRI, correlates with a greater value of inflammation markers and greater physician global assessment (PGA) score. Through blood samples and MRI scans, ESR/CRP values and number of active lesions within 30 days of the visit were recorded. General statistical methods were used to summarize the data and determine correlation. We expect a strong positive correlation between active lesion count and ESR/CRP values. ESR/CRP values measure the rate of inflammation. As inflammation is a common physiological symptom stemming from lesion presence, a positive correlation between these variables must occur. Additionally, we expect a strong positive correlation between active lesion count and PGA scores. PGA scores are determined during clinical visits and are drawn from assessing a patient’s current condition. The prominence/severity of lesions are factored into the PGA score. As CNO lacks a reliable technique to monitor the disease, we expect that the results from this study will shed light on a reliable and robust assessment tool to monitor disease activity.