Functional Genomics is the study of cellular events that link genotype to phenotype. In other words, we determine the cellular mechanisms through which genetic changes cause diseases. Due to the incredible complexity of cell regulation and molecular interactions, functional genomics requires laboratory methods capable of measuring molecular events on a genome-wide scale. We are using state-of-the-art genomics technology and bioinformatics to characterize cellular mechanisms that link genomic mutations and epigenetic events to disease onset and progression. The ultimate goal of our research is to understand the disease process at the molecular level so that we may develop improved therapeutics and diagnostics.
Areas of Research
microRNAs are short, non-coding nucleic acids that are involved in the regulation of most cellular processes. They exert their regulatory effect by binding to complementary regions in target messenger RNA (mRNA), resulting in either degradation of the mRNA or inhibition of mRNA translation to protein. Mature microRNAs are typically 22 nucleotides in length and are very stable compared to longer RNAs. Their notable stability, presence in virtually all body fluids, and frequent expression changes associated with diseases have created much interest in using microRNAs as diagnostic biomarkers. Furthermore, there is considerable interest in using microRNAs in therapeutic applications.
We are investigating the role of microRNAs in the onset of seizures in pediatric patients with tuberous sclerosis complex (TSC). In this project we are identifying microRNAs with aberrant expression levels in epileptogenic brain tissue that was surgically resected to treat intractable epilepsy. We then use computational methods to identify targets and quantitative proteomics (LC-MS/MS) to measure changes in abundance of proteins that are targeted by the aberrant microRNAs.
Modifications to DNA are an important mechanism of cell regulation. Methylation of cytosines in DNA (5 methylcytosine, 5mC) is known to cause gene "silencing" and is involved in normal development, as well as in diseases. When 5mC is further modified to 5-hydroxymethylcytosine (5hmC) then the regulatory role of the modified cytosine is also changed. The mechanisms through which 5hmC regulates cell processes are just being uncovered. The brain has much higher levels of 5hmC compared to other organs, but the role of 5hmC in neurological processes is not well understood. We are using functional genomics techniques and bioinformatics to explore the role of 5hmC in the onset of epilepsy in tuberous sclerosis complex patients.
We are using next generation sequencing (NGS) technology to identify disease-causing mutations in genes and their regulatory regions. Our projects include the investigation of mutations involved in the brain pathology of tuberous sclerosis complex (TSC) patients. Mutations in the TSC1 and TSC2 genes are known to cause TSC; however, it is suspected that other genes could also be involved.
There is great need for accurate, non-invasive diagnostic methods to detect the onset, progression, and treatment response for a wide range of diseases. We use functional genomics methods to perform genome-wide analyses for the identification of molecules that can be easily measured and indicate the presence of a disease condition. Among these molecules, microRNAs show great potential due to their stability and presence in most body fluids. We are investigating microRNA biomarkers that can be detected in blood and cerebral spinal fluid.