Cilia Dysfunction, Brain Dysplasia, and Neurodevelopmental Outcome in Congenital Heart Disease
Abstract
Structural defects involving the heart, also known as congenital heart disease (CHD), are the most common type of birth defects, seen in nearly 1% of live births. Surgical advances now allow most patients with CHD to survive, resulting in an ever-increasing population of adults with CHD. Indeed, currently there are more adults with CHD than infants born each year with CHD. As intellectual and neuropsychiatric disabilities are the most common and disabling long-term complication of congenital heart defects, research into the causes of the poor neurodevelopmental outcome of CHD patients has become a critical priority. In this project, we will investigate the novel hypothesis that CHD patients with defects involving the cilia are at high risk for brain abnormalities and neurobehavioral and neurocognitive deficits. For these studies, we will recruit CHD patients and healthy controls and assess for ciliary dysfunction (CD). Brain MRI (magnetic resonance imaging) and neurocognitive assessments will be conducted. Cilia are hair-like protrusions found at the cell surface that can be motile or non-motile. For these studies, we will take advantage of patient-derived cells and tissue to directly assay both motile and primary cilia function. Motile cilia in the brain play important roles in driving cerebral spinal fluid flow required for supporting neural cell migration and sustaining metabolic function in the brain. As motile cilia are also found in the airway where they help eject mucus and debris to maintain lung health, tissue obtained from nasal scrape can be used to examine motile cilia function in the airway as a proxy for motile cilia in the brain. This analysis showed a surprisingly high prevalence of airway CD in patients with CHD. Importantly, CHD patients with CD also exhibited a high incidence of brain dysplasia, and this was associated with learning and memory deficits. Together, these findings support a role for CD in the poor neurodevelopmental outcome seen with CHD. Using patient cells obtained from the nasal tissue explants, we will further assess primary cilia transduced Shh signaling. These studies are compelling, given regions exhibiting brain dysplasia in CHD patients are also regions known to be dependent on Shh signaling. These same regions of the brain also undergo adult neurogenesis in a Shh-dependent manner. That CHD patients with motile cilia defects might also have primary cilia defects is not surprising, given 75% of proteins in motile cilia are also found in non-motile primary cilia. Hence, making novel use of patient derived cells, we will be able to assess for motile and primary cilia defects. These ciliary function assessments will be combined with brain MRI and neurocognitive and neurobehavioral assessments, and together, these studies will help determine if CD in CHD patients is predictive of poor neurodevelopment outcome. The new mechanistic insights gained from these studies may provide a new pathway for personalized medicine with improved precision in risk stratification of CHD patients. If our hypothesis is validated, it would suggest a change in the standard of care to include early screening with nasal scrapes to identify CHD patients with CD and hence high neurodevelopmental risks. This risk stratification would allow the targeted use of brain MRI and neurocognitive assessments on the most vulnerable CHD patient population. CHD patients subsequently confirmed to have brain dysplasia and neurobehavioral/neurocognitive deficits could be provided early intervention with behavioral and cognitive therapies. Such early therapeutic intervention is well documented to be highly effective in improving the neurodevelopmental outcome of patients with a broad spectrum of neurocognitive and intellectual disabilities, including those with autism, ADHD and other neuropsychiatric disorders. Furthermore, should our studies confirm a link between disruption of Shh signaling and adve
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610613
Entities
People
- Cecilia Lo
Organizations
- United States Army
- University of Pittsburgh