The major focus of the Wilhelm lab is the molecular mechanisms underlying learning and memory and how they are perturbed in inherited or congenital brain diseases. We use a variety of in vitro and in vivo tools to study synaptic and dendritic biology to elucidate these mechanisms. The ultimate goal of this research is to improve the neurodevelopmental outcomes of children with both congenital and acquired forms of central nervous system injury. These efforts are imperative because neurodevelopmental disabilities remain the primary negative consequence of critical illness in infants and children despite ever-improving mortality rates for our sickest patients.
Regulation of Dendritic Proteins by Synaptic Activity
Long-term potentiation (LTP) and long-term depression (LTD), the electrophysiological correlates of memory, require rapidly induced, long lasting changes in synaptic proteins in response to neuronal activity. Our lab is currently investigating how the c-Jun N-terminal kinase (JNK) pathway is involved in regulating protein turnover within dendritic spines in response to metabotropic glutamate receptor activation and how this regulates synaptic function. Current translational research efforts are focusing on how this pathway is altered in Fragile X Syndrome. Fragile X Syndrome is the most common inherited cause of mental retardation and provides a “clean” (single gene deletion) model in which to study these molecular signals.
We use synaptoneurosomes (SNs) to study the turnover of dendritic proteins in the absence of nuclear gene regulation. We also use confocal immunomicroscopy to determine local signaling events in dendritic spines in intact, cultured neurons. Electrophysiologic studies and behavioral testing are used to determine the consequences of the molecular events identified in these studies. We are also interested in how acquired CNS injuries (hypoxia-ischemia, HI) in the developing brain affect these pathways. Our lab is housed within the Waisman Center, one of nine national facilities that includes a Eunice Kennedy Shriver Intellectual and Developmental Disabilities Research Center and a University Center for Excellence in Developmental Disabilities. This allows collaboration with other basic and clinical scientists studying FXS and neonatal HI.
Molecular Mechanisms of Hypertrophic Cardiomyopathy (HCM) and Heart Failure
Our lab collaborates with Dr. Carter Ralphe in Pediatric Cardiology investigating the cellular signaling events that occur in cardiomyocytes subjected to genetic and environmental stressors. Cardiomyopathy from a variety of insults may ultimately lead to heart failure and this may be due in part to apoptotic death of cardiomyocytes. Several hypertrophic signaling events may promote pro-apoptotic signaling, and one such pathway is the c-Jun N-terminal kinase (JNK) pathway. Our lab is investigating the regulation of the JNK pathway in normal cardiomyocytes and those genetically pre-disposed to hypertrophic cardiomyopathy. Understanding how stress signaling contributes to the ultimate pathobiology of HCM and heart failure will have important implications for the treatment of patients and their family members who carry these mutations.
Improving Fellowship Education through Interactive Sessions
Dr. Wilhelm is the director of the fellowship program and he has developed a comprehensive curriculum for the fellows that relies on interactive, case-based sessions instead of didactic lectures. Educational research efforts center on the integration of novel technologies within this curriculum to enhance trainee-directed learning.