Neurodevelopmental abnormalities and congenital heart disease
In the past 2-3 decades, it has become evident that individuals born with congenital heart disease (CHD) are at risk of developing life-long neurological deficits. Multifactorial risk factors contributing to neurodevelopmental abnormalities associated with CHD have been identified; however, the underlying causes remain largely unknown, and efforts to address this issue have only recently begun. We investigate the dynamic nature of cellular events and how CHD may adversely impact the cellular units and networks necessary for proper cognitive and motor function. Ultimately, a multidisciplinary approach will be essential to prevent or improve adverse neurodevelopmental outcomes in individuals surviving CHD.
Review: Circulation Research 2017
Congenital cardiac anomalies and white matter injury
Derangement of circulatory flow affects many vital organs; without proper supply of oxygenated blood, the brain is particularly vulnerable. Although surgical interventions have greatly reduced mortality rates, patients often suffer an array of neurological deficits throughout life. Neuroimaging provides a macroscopic assessment of brain injury and has shown that white matter is at risk. Oligodendrocytes and myelinated axons have been identified as major targets of white matter injury, but still little is known about how congenital heart anomalies affect the brain at the cellular level. Further integration of animal model studies and clinical research will define novel therapeutic targets and new standards of care to prevent developmental delays associated with cardiac abnormalities.
Review: Trends in Neuroscience 2015
Cortical dysmaturation in congenital heart disease
Emerging evidence indicates that cardiac anomalies lead to a reduction in cerebral oxygenation, which appears to profoundly impact on the maturation of cerebral regions responsible for higher-order cognitive functions. We study the potential mechanisms by which dysregulation of cortical neuronal development during early life may lead to the significant cognitive impairments that commonly occur in children with CHD. Further understanding of the mechanisms underlying cortical dysmaturation due to CHD will be necessary to identify strategies for neonatal neuroprotection and for mitigating developmental delays in this patient population.
Review: Trends in Neuroscience 2019
Nonapoptotic caspases in neural development and in anesthesia-induced neurotoxicity
Apoptosis, classically initiated by caspase pathway activation, plays a prominent role during normal brain development as well as in neurodegeneration. The noncanonical, nonlethal arm of the caspase pathway is evolutionarily conserved and has also been implicated in both processes yet is relatively understudied. Dysregulated pathway activation during critical periods of neurodevelopment due to environmental neurotoxins or exposure to compounds such as anesthetics can have detrimental consequences for brain maturation and long-term effects on behavior. We study both genetic and environmental factors that regulate apoptotic and sublethal caspase responses and investigate potential interventions that target the noncanonical caspase pathway for developmental brain injuries.
Review: Trends in Neuroscience 2022
The role of primary cilia in congenital heart defect-associated neurological impairments
In the past few decades, it has become clear that CHD is highly genetically heterogeneous, with large chromosomal aneuploidies and copy number variants (CNVs) as well as single nucleotide polymorphisms (SNPs) being implicated in CHD pathogenesis. Intriguingly, many of the identified loss-of-function genetic variants occur in genes important for primary cilia integrity and function, hinting at a key role for primary cilia in CHD. We study the role of environmental exposures in CHD, including stressors such as surgical factors and anesthesia, and how they might interact with ciliary genetic predispositions to determine the final neurodevelopmental outcome.
Review: Frontiers in Genetics 2024
Mesenchymal stromal cell Delivery through Cardiopulmonary bypass in Pediatric cardiac surgery (MeDCaP Single-site Safety Trial)
The translational nature of our program has led to significant milestones, including the development of the NIH-funded Phase 1 clinical trial. This trial confirmed the safety and feasibility of a cell-based therapeutic approach.