Investigation of Neurodevelopment Concomitant with Cardiovascular Hemodynamic Function in Genetically Engineered Mouse Models of Hypoplastic Left Heart Syndrome
Abstract
This proposal addresses the Peer Reviewed Medical Research Program topic area “Congenital Heart Disease” (CHD). CHDs are the most common birth defects, affecting nearly 1%, or about 40,000, of births per year in the United States; many of these are in military families. With the advancement of reconstructive heart surgery, the survival rate for children with CHD has greatly improved for the past two decades. Most children born with CHD today can reach adulthood. However, even after successful heart reconstruction surgery, many children born with CHD suffer from long-term learning and memory deficits as well as developmental delays. Currently there are no good clinical treatments to help children and adult patients with CHD because the reasons that CHD patients suffer from long-term neurodevelopmental problems are not understood. Therefore, it is important to understand the causes of neurodevelopmental deficits seen in CHD patients in order to develop more effective treatment and therapeutic strategies. Currently more people believe that the neurological problems in CHD patients come from the compromised blood flow and oxygenation in the fetal stage due to the structural heart defects. Thus, there are fetal therapeutic strategies being developed to try to increase the blood flow or oxygenation in the placenta, hoping to improve the brain development. However, some new evidences showed that there are intrinsic genetic factors that drive the neurodevelopmental abnormality in CHD patients. The goal of this study is to investigate if there are intrinsic genetic factors that contribute to the neurodevelopmental abnormality in CHD. We propose to study the structure-function relationship in the heart and the brain of the same fetuses throughout fetal development to determine if the genetic or cardiovascular factors drive the neuronal defects. We will perform the investigation in genetically engineered mouse models that displayed various CHD, including the hypoplastic left heart syndrome (HLHS), one of the most devastating CHDs, as well as other complexed CHDs. We have developed a new cutting-edge fetal magnetic resonance imaging (MRI) method that will allow us to image both fetal brain and heart simultaneously on the same mouse fetuses throughout the development to determine whether cardiovascular deficits are the driving force for the brain defects. We will correlate the fetal MRI finding with genetic analysis, as well as ultrasound and other postmortem validation to confirm and cross-examine our fetal MRI findings. In addition, we will examine if the developmental delays in the mutant mouse brains will resolve as the animals grow older. The success of this project will provide the basis to investigate the integration of structure-function in heart and brain development for new insights into cardiovascular influences on neurodevelopment in the pathogenesis of CHD patients. In addition, it can be a fast technique for comprehensive multi-parameter fetal assessment and intervention planning for other types of congenital defects. It will also point to new directions for clinical management and therapeutic strategies for CHD patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810070
Entities
People
- Yijen Wu
Organizations
- United States Army
- University of Pittsburgh