Dates of funding: 2020-2022

My specialized clinical training in pediatric gastroenterology and nutrition has cultivated my research
passion to understand how nutrition contributes and affects clinical outcomes of pediatric patients with
inflammatory bowel disease (IBD) which includes Crohn’s disease (CD) and ulcerative colitis (UC).

My research to date has focused on the regulation of utero-placental function by environmental and endocrine factors and its role in the determination of fetal growth and offspring health. This interest began at the Centre for Trophoblast Research at the University of Cambridge. During my PhD I gained extensive experience of in vivo techniques in rodents, including experiments in pregnant animals and large-cohort, multigenerational studies investigating the feto-placental effects of glucocorticoids. In this period, I also obtained proficiency in gene and protein expression and morphometric analyses. I continued my research in this area during postdoctoral training at Cambridge, gaining additional experience of large animal metabolic studies and chronic catheterization techniques in sheep whilst also investigating more deeply the molecular actions of glucocorticoids in the placenta as part of a transcriptomic and bioinformatic project funded by a personal award from the British Society for Endocrinology. My rodent studies culminated in the publication of a series of papers on placental function during maternal stress which garnered interest in the scientific and UK national press. Subsequently, I took up a second postdoctoral position at University College London working upon a more translational project, aiming to develop a therapy for severe intrauterine growth restriction by targeting gene therapy to the uterine arteries in pregnant women. As part of this project, I expanded my expertise in cardiovascular physiology, overseeing protocols for measurement of blood pressure and cardiac morphology in guinea pigs. I moved to the University of Colorado in 2016 in order to gain additional experience in translational reproductive science, in particular capitalizing upon the enhanced opportunities for collaboration with clinical colleagues and access to human tissue available at Anschutz Medical Campus. As a result of this research, I have published 21 research papers (10 first author, including 2 based on my work in Colorado), 8 review articles and over 20 conference papers since 2010. The focus of my current research is the molecular mechanisms by which offspring cardiac dysfunction is programmed in utero in maternal obesity and I have recently reported that normalization of maternal adiponectin levels in obese pregnant mice prevented the development of diastolic dysfunction.  Thus, my research links maternal obesity and nutrition during pregnancy with the long term programming of metabolic disease in children.

The overall goal of my research program is to understand the biological mechanisms by which exercise, sleep, and nocturnal metabolism influence risk for cardiovascular disease, diabetes, and obesity. Sleep has emerged as a key behavior that influences the risk of obesity and obesity related co-morbidities (e.g., diabetes, cardiovascular disease). During sleep, there are many dynamic changes in hormones and metabolites, such as secretion pulses in growth hormone and oscillations in glucose concentrations. Recent studies by my mentors have demonstrated that nocturnal free fatty acid concentrations and nocturnal fat oxidation are related to next day insulin sensitivity and risk for future weight gain. Further, disruptions in sleep quality, independent of sleep quantity, may cause many impairments in metabolism (e.g. insulin resistance, hyperglycemia) and increase the risk of weight gain. Collectively, these data indicate that nocturnal fat metabolism and sleep quality are related to clinically relevant health outcomes and represent an important and understudied area in the field of nutrition and obesity research.

Individuals with obesity and metabolic syndrome (MetS) have an increased risk of chronic disease and frequently report sleep problems. Disrupted sleep quality may exacerbate the metabolic defects already present in individuals with MetS, thus, determining methods to positively impact sleep in this population is of great importance. Exercise has been a cornerstone of behavioral modifications to treat obesity for decades. There is evidence to suggest exercise improves sleep quality in healthy populations. However, the effect of exercise on sleep quality in individuals with underlying metabolic disease (e.g. obesity, MetS) is not known. Understanding whether exercise positively impacts sleep quality in this population is key in managing chronic disease risk. My current research is investigating how exercise impacts sleep quality and nocturnal metabolism in individuals with MetS.  I expect my findings will provide insight into how exercise and sleep interact to reduce chronic disease risk.

Dates of funding: 2018-2019

Diabetes affects more than 20 million people in the United States, or roughly 1 of out 11 individuals and obesity-induced diabetes incidence is steadily increasing. Despite great efforts, there is unfortunately still no cure. The best treatments for the disease require constant and diligent patient management and even when managed appropriately, the disease can still lead to serious complications like heart disease, blindness, and amputation. We have long known that obesity is a great risk factor for diabetes, however, many of the disrupted genetic pathways that contribute to the disease are still unknown. My proposal seeks to identify novel molecules involved in the onset and/or progression of diabetes with the ultimate goal of discovering effective therapeutics for the many patients affected by diabetes. In particular, I am focusing on a novel class of molecules called long non-coding RNAs (lncRNAs), which were previously unknown to be important in biology, but contain properties that facilitate therapeutic targeting. In this study, I have identified a new lncRNA that becomes highly upregulated in the β cells of several obese-diabetic mouse models and islets from obese diabetic patients. We hypothesize that this lncRNA is important for the onset and/or progression of diabetes and we propose a set of studies to determine its specific role during disease development and assess whether targeted disruption of its expression can improve β cell function and patient outcomes.

Dates of Funding: 2017-2019
Assistant Professor, Department of Health and Exercise Science, Colorado State University Assistant Professor, Division of Endocrinology, Metabolism and Diabetes, University of Colorado, Anschutz Medical Campus

The Impact of Insufficient Sleep on Peripheral Metabolic Tissues

Short nightly sleep duration and untreated sleep disorders are now recognized as risk factors for metabolic diseases with more than 35%of Americans sleeping less than the recommended 7 hours/night. Acute, experimental sleep restriction studies have demonstrated inadequate sleep alters glucose homeostasis, primarily by decreasing whole-body insulin sensitivity. However, the mechanisms responsible for the adverse effect of sleep restriction on insulin sensitivity are not known and understanding the effects of sleep restriction on other metabolic tissues is in its infancy. Our long-term goal is to demonstrate the importance of adequate sleep duration and to establish sleep as a third pillar of health—in addition to diet and exercise—in the maintenance of cellular, tissue and whole-body metabolic homeostasis. The overall objective for this project is to determine how insufficient sleep impairs insulin sensitivity in peripheral metabolic tissues biopsied from healthy young lean men and women after normal and insufficient sleep.

Dates of Funding to: 2016-2019

PTH and Calcium responses to Exercise in Older Adults (PACE Sr.)

Age-related increases in osteoporotic fracture are associated with a large healthcare burden. Weight-bearing exercise is recommended to prevent osteoporosis, but emerging evidence indicates exercise may not always result in osteogenic benefit. Preliminary work suggests calcium losses during exercise triggers increases in bone resorption and are attenuated by calcium supplementation. Therefore, the global aim is to investigate nutritional contributions to calcium homeostasis, including calcium needs during exercise. SA1 will determine if preventing serum ionized calcium (iCa) declines during exercise prevents increases in bone resorption. Participants will complete walking bouts under conditions of 1) intravenous calcium infusion (prevent iCa decline) and 2) volume-matched saline infusion. We hypothesize that exercise will stimulate resorption to stabilize iCa concentration more under the saline condition. Additionally, SA1 will measure calcium infusion amounts needed to prevent iCa declines. SA2 will determine how bisphosphonate medication impacts this relationship. Bisphosphonates diminish osteoclast activity, which is believed the be the cell primarily responsible for bone resorption during exercise. However, if bone resorption still increases during exercise, this would suggest that the osteocyte contributes to calcium homeostasis. To our knowledge, this will be the first study investigating osteocytic osteolysis in vivo in humans. Combined, these experiments will inform future supplementation trials to determine calcium recommendations. Long-term, this may lead to improved bone adaptations and reduced osteoporosis-related incidents.

Dates of funding 2017-2019

Impact of dietary nitrate supplementation via beetroot juice on skeletal muscle metabolic control and exercise tolerance in sickle cell anemia

Sickle Cell Disease results in severely compromised exercise capacity, and thus the quality of life, for those afflicted. This is due to both central cardiopulmonary and peripheral vascular factors which conspire to reduce maximal oxygen uptake (VO₂max) and instill premature fatigue during exercise. SCD results in high rates of hemolysis and the resulting release of free-hemoglobin (HB) rapidly scavenges nitric oxide (NO) resulting in impaired cardiovascular control. Our work focuses on the impact of Hb on skeletal muscle vascular and metabolic control as this is likely a primary mechanism of peripheral vasculopathy and exercise decrement in SCD.

Over the past decade, a plethora of investigations have demonstrated the robust efficacy of dietary nitrate supplementation in the treatment of many prevalent diseases related to loss of NO bioavailability; accordingly, it has been hailed as an “unrecognized nutrient.” Previous investigations in humans and animals have demonstrated that NO₃^–, when consumed, serves as a powerful controller of muscle O₂perfusion, presumably following its reduction to nitrite (NO₂^–) and NO in vivo. Collectively, these results strongly support the premise that dietary NO₃^– as a nutritional therapeutic will ameliorate Hb-mediated NO depletion for patients with SCD, and therefore evoke improved exercise tolerance and quality of life. Thus, this project is aimed at uncovering the mechanistic basis for skeletal muscle dysfunction in SCD and the therapeutic potential of dietary NO₃^– in preclinical models of this disease. Results from these investigations will directly impact the design of future clinical studies at the University of Colorado, Denver in the coming years.

Dates of funding: 2018-2019

University of Colorado, Anschutz Medical Campus · Obstetrics and Gynecology Department, Division of Reproductive Sciences

Dates of funding: 2020-2022

I am currently an Assistant Professor at the University of Colorado-Anschutz Medical Campus (CU AMC) in the Division of Endocrinology, Metabolism, and Diabetes. I hold an NIH Career Development Award (K01 HL145023) investigating the extent to which patterns and timing of behaviors (physical activity, food intake, and sleep) influence body weight regulation. To date, my career has focused on identifying and improving strategies to treat and prevent overweight and obesity by linking behavioral and bioenergetic outcomes. My NORC pilot project aligns with my career focus as it seeks to examine the effects of exercise timing on weight loss and components of energy balance (energy expenditure and energy intake). This pilot study stems from our prior findings that morning and evening exercise result in different amounts of weight loss. We hope that this preliminary work will lead to future clinical and mechanistic studies on how the timing of exercise affects energy intake, energy expenditure, sleep, and ultimately body weight regulation.

Dates of funding: 2020-2022

I am an Assistant Professor at the University of Colorado Anschutz Medical Campus in the Division of Endocrinology, Metabolism, and Diabetes and a VA research scientist at the Rocky Mountain Regional VA Medical Center. The objective of my research is to better understand the diabetes burden in premenopausal women through the investigation of the cycle between type 2 diabetes and estrogen signaling. The primary themes of my research program are 1) to determine the interaction of diabetes and estrogen signaling on skeletal muscle mitochondria and 2) to elucidate the mechanisms by which endocrine therapies for breast cancer increase type 2 diabetes risk in cancer survivors. I am currently funded by a VA Career Development Award (CDA2) to investigate the interaction of diabetes and estrogen on metabolic flexibility and exercise tolerance in rats with hyperglycemia and hyperinsulinemia. My NORC pilot project aligns with my research program and provides added value to my CDA2 by exploring how the diabetic environment alters the gene expression signature associated with estrogen in skeletal muscle. The goal for the data generated with this NORC pilot award is to identify potential therapeutic targets in estrogen signaling that are disrupted in women with type 2 diabetes.

Dates of funding: 2020-2022

My research interests lie in understanding to the contribution of endoplasmic reticulum (ER) health and unfolded protein response (UPR) in maintaining skeletal homeostasis in physiologic and pathological conditions. I have broad background and training in the domains of genetics, molecular biology, microscopy, skeletal biology and mechanistic studies in osteoporosis. I have extensive experience in generating and leveraging conditional mice knockouts relevant for studying mechanisms of bone loss in osteoblast lineage cells. During my post-doctoral training, I focused on understanding mechanisms that mediate bone loss with sex steroid deficiency and age and role of senescence as their mediator. Specifically, I examined the role of FoxO family of transcription factors and sex hormones and their receptors in skeleton in particularly in osteoblast progenitor cells. As a faculty at University of Arkansas Medical Sciences, I generated genetic mouse models to specifically address the role of UPR sensors in osteoblast lineage cells and bone health. I was funded by P20 NIGMS COBRE project as junior PI in Arkansas for one year, during which I developed expertise in various microscopy techniques for imaging bone including TEM to visualize ER of osteoblasts on tissue sections. In the context of this proposal, I will focus on the effects of high-fat diet on osteoblast progenitor cells and actions of the UPR sensor Perk in these cells as a contributor to obesity-related skeletal changes. The present application leverages my strong background in osteoblast biology to examine the role of fundamental cellular pathways to define the molecular basis of skeletal fragility in setting of obesity.