Garcia Lab
Aurora, CO
OUR RESEARCH
We are a basic and translational science research lab in the Department of Pediatrics, section of Cardiology at the University of Colorado - Anschutz Medical Campus and Children’s Hospital Colorado.
Our research focuses on pediatric cardiovascular and congenital heart disease with particular emphasis on investigations of the molecular mechanisms underlying the remodeling of cardiac and immune cell metabolism, identification of novel therapeutic targets, and biomarker assessment. The ultimate goal of this research is to develop the critical knowledge base and infrastructure necessary to identify efficacious therapies for improving outcomes in patients with heart disease. The lab utilizes several unique tools to address the mechanisms of cardiac dysfunction including whole animal and cell culture-based models, as well as a meticulously preserved Pediatric Heart Tissue and Blood BioBank.
Additionally, we collaborate with a variety of labs to assess parameters of mitochondrial bioenergetics in several different physiologic and pathologic processes
WHY?
Congenital heart defects are the most common birth defect and the leading cause of infant death in the US
Congenital heart disease is 60 times more prevalent than childhood cancer
1 out of every 100 babies is born with a congenital heart disease every 15 min in US
It is estimated that 2-3 million children and adults are living with congenital heart disease in the US today
25% of all babies born with a congenital heart defect are born with a severe congenital heart disease, requiring immediate intervention
The most common severe congenital heart disease is Single Ventricle Congenital Heart Disease (SV), with the prototypical case being Hypoplastic Left Heart Syndrome (HLHS)
There are limited treatment options for patients with HLHS and other SV defects, and traditional adult heart failure therapies have failed to elicit benefit
Patients with single ventricle defects have a higher risk of mortality than patients with any other congenital heart disease, in fact, more than 30% of SV patients die or require transplant in their 1st year, and 10-year survival is only 39-50%
Therefore, there remains a critical need to better understand the mechanisms of SV failure, and to identify clinically relevant pathways, biomarkers of disease progression, and novel therapeutic targets.
Patients born with HLHS, illustrated below, display severe underdevelopment of left sided heart structures including the left ventricle (pumping chamber), mitral valve (between the left atrium and left ventricle), and aortic valve (between the left ventricle and aorta).
OUR CURRENT PROJECTS
Fluorescent Image of Human HLHS Cardiac Tissue
Glycosphingolipid-Mediated Cardiomyocyte and Immune Cell Dysfunction in Hypoplastic Left Heart Syndrome
Hypoplastic left heart syndrome (HLHS) is the most common severe congenital heart disease and is both the leading indication for heart transplantation in infancy and the most common cause of cardiovascular death in infants. With improved understanding of HLHS pathogenesis, the identification of novel therapeutic strategies will serve to decrease costs and improve outcomes for this vulnerable group. Unfortunately, very little is known about how the failing HLHS heart differs from the failing adult biventricular heart, but the extrapolation of proven adult heart failure medications to the HLHS population has been unsuccessful, suggesting focused study is necessary to better understand the mechanisms underlying maladaptive remodeling and eventual heart failure in HLHS. Our preliminary data suggest glycosphingolipids (GSLs) play a role in modulating cardiomyocyte and immune cell function in HLHS, via both autocrine and paracrine signaling. Therefore, our central hypothesis is that aberrant glycosphingolipids drive maladaptive cardiac and immune cell responses and predispose HLHS patients to life-limiting complications including cardiac dysfunction. The results of this study will establish key mechanisms and modulators of heart failure progression in HLHS and will elucidate a potential therapeutic pathway to mitigate cardiometabolic impairments and progressive cardiac dysfunction in this vulnerable population. This work is funded by an R01 from the NIH – National Heart Lung and Blood Institute; Principal Investigator: Anastacia “Tasha” Garcia, PhD
Brightfield image of Human HLHS Peripheral Blood Immune Cells
Consequences of Impaired T Cell Homeostasis in Single Ventricle Congenital Heart Disease
Staged surgical palliation for infants born with single ventricle (SV) congenital heart disease has enabled many patients to survive a previously fatal condition. However, there is now a growing population of SV children and young adults who experience significant co-morbidities and mortality secondary to their palliated physiology. Failed SV palliation encompasses a variety of clinical pathologies with downstream, multi-organ consequences which ultimately result in an increasing number of SV patients requiring heart transplant. Unfortunately, the mechanisms underlying development of heart failure and other significant co-morbidities in SV patients are poorly understood. The overall objective of this proposal is to study how existing immune dysfunction may drive further complications in single ventricle patients. Our central hypothesis is that an activated and exhausted T cell phenotype predisposes SV patients to complications including progressive cardiac dysfunction. This work is funded by Additional Ventures and the American Heart Association’s Collaborative Sciences Award; Principal Investigators: Stephanie Nakano, MD, Anastacia “Tasha” Garcia, PhD, Julie Lang, PhD, and Jordan Abbott, MD.
Additionally, due to our expertise in mitochondrial bioenergetics, we have several ongoing collaborative projects, including:
Fluorescent image of Isolated [mouse] Brain Vasculature; Image credit: Danielle Jeffrey, MS
Brain capillary endothelial cell energetics and neurovascular uncoupling in dementia
Growing evidence suggests the contribution of altered brain microcirculation to cognitive impairment and dementia observed in Alzheimer's disease (AD) and AD-related dementia (ADRD). Yet, the lack of approaches to image and investigate the function of the small cerebrovasculature has hampered our progress in understanding the pathological sequence of vascular cognitive impairment and dementia (VCID). Our multidisciplinary team, with complementary expertise in cutting-edge imaging of brain microcirculation and bioenergetic approaches, will test the hypothesis that alterations in the extracellular matrix inhibit autocrine activation of the epidermal growth factor receptor (EGFR) leading to mitochondrial dysfunction and lower ATP production in CADASIL but also in presence on Aβ oligomers. We further propose to investigate this pathomechanism in humans using freshly isolated brain microvessels paired with spatial and single cell transcriptomics in human autopsy brain tissue. To attain this goal, we will engage a wide variety of novel, state-of-the-art experimental approaches using intact animals, native tissue, and freshly isolated cells, complemented by sophisticated multi-omics analysis. The proposed work has the potential to provide a paradigm-shifting view on how capillary endothelial cell energetics control neurovascular coupling, and as such, should provide the foundation for understanding VCID development that is necessary to identify novel efficacious therapeutic strategies. This work is funded by a multi-PI R01 from the NIH - National Institute of Neurological Disorders and Stroke; Principal Investigators: Fabrice Dabertrand, PhD and Anastacia “Tasha” Garcia, PhD.
Defining cardiac mitochondrial and sarcomeric responses to estradiol replacement in aged females
Diastolic dysfunction is a condition where cardiac relaxation is impaired leading to inadequate cardiac output. After menopause, women have a higher risk of developing diastolic dysfunction, but it is not clear what mechanisms lead to this change in propensity. We developed this proposal to assess the effect of estradiol on cardiomyocyte bioenergetic and biomechanical function, and the bi-directional mitochondrial– sarcomeric crosstalk between these organelles in the context of estradiol manipulation. We hypothesize that lower estradiol in the myocardium decreases mitochondrial oxidative phosphorylation, and this dysfunction is relayed to the sarcomere via shifts in metabolite pools, which induce differential acylation profiles on sarcomeric proteins; thereby regulating sarcomeric function. This work is funded by an Interdisciplinary multi-PI research award from the Ludeman Family Center for Women’s Health Research; Principal Investigators: Kathleen “KC” Woulfe, PhD and Anastacia “Tasha” Garcia, PhD.
Many thanks to those agencies and organizations who have generously funded our research efforts over the years, enabling us to advance our knowledge and make significant contributions to our field.