The Pediatric Neuropathology/Neurogenetic Diseases Laboratory conducts research focused on two major disorders associated with intellectual disability: the neuronal ceroid lipofuscinoses (NCLs), constituting collectively the most common neuronopathic lysosomal storage disorder, and Down syndrome, the most frequent genetic cause of intellectual disability. The long-term goal of the laboratory is to identify the pathomechanisms leading to neurodegeneration and, subequently, dysfunction of the central nervous system in both of these disorders as a first step to developing effective methods of treatment for affected individuals.
The Monoclonal Antibody Facility (MAF) is dedicated to the design, generation, and utilization of monoclonal antibodies (mAbs). mAb molecules produced in the laboratory can specifically identify protein markers associated with various forms of developmental disabilities. These molecules afford the specificity and sensitivity required for research, diagnosis, and therapeutic applications.
Current projects of the Pediatric Neuropathology/Neurogenetic Diseases Laboratory include:
- Characterization of how knockout (a technique in which one of an organism's genes is made inoperative) of tripeptidyl peptidase 1, a lysosomal enzyme associated with the classic late infantile form of NCL (CLN2), and the resulting accumulation of lysosomal storage material affect lysosomal function and signaling pathways leading to cell death. These studies are being conducted by using a neuronal cell culture model for CLN2 (CRISPR/Cas9 system) that we developed.
- Detection of molecular mechanisms underlying pathogenic missense mutations in tripeptidyl peptidase 1 and identification of factors and conditions that can ameliorate the functional consequences of these mutations.
- Delineation of molecular mechanisms and signaling pathways that underlie significant improvement of cognitive functions and motor skills in TS65Dn mice, a mouse model for trisomy 21 (Down syndrome), after environmental stimulation (prolonged voluntary running), which we had documented earlier.
Currently, the Monoclonal Antibody Facility (MAF) laboratory focuses on the diagnosis of Fragile X syndrome, autism, and Down syndrome/Alzheimer’s disease. The MAF is also investigating treatment/therapeutic approaches using many of our mAbs, especially those related to Down syndrome/Alzheimer’s disease. The success of this approach may lead to strategies to combat other forms of developmental disabilities. This strategy involves the generation of mAbs to the three-dimensional structure (discontinuous epitopes) of disease-related proteins. Many of the mAbs generated by the MAF are marketed by Biolegend, Inc., and EMD Millipore Corp., generating funds to support many projects within the Monoclonal Antibody Facility and the IBR community.