Psychiatric disorders are not only often debilitating for the individuals affected, but can also serve as models for disturbances in complex human behaviors. They are often associated with neuroanatomical changes in affected patients. My own research focuses on the identification of these brain structural changes and their molecular underpinnings. To address these scientific questions, my lab utilizes a broad methodical spectrum ranging from magnetic resonance imaging (MRI) and the systematic application of brain mapping tools in humans to the utilization of animal models and the identification of susceptibility pathways.
Research in the Abel lab focuses on the molecular mechanisms of memory storage and the molecular basis of neurodevelopmental and psychiatric disorders. We use mouse models to examine the role of molecular signaling pathways as well as transcriptional and epigenetic regulation of gene expression in defining how neural circuits mediate behavior.
The Williams Lab is interested in understanding the molecular and cellular mechanisms by which genetic risk factors contribute to psychiatric disease from a developmental perspective. Their current projects focus on voltage-gated calcium channel genes, which have been linked to the risk of developing bipolar disorder, schizophrenia, depression, and autism. They use induced pluripotent stem cells and transgenic mouse models to study how calcium channel gene SNPs alter neuronal development, neural circuit function, and affective behavior.
My primary research interest is in the genetic determinants of intellectual disability (ID), formerly referred to as mental retardation (MR). I specifically study the roles of copy number variation and somatic structural variation in the context of a “genomic mutational burden” hypothesis of ID. This hypothesis is investigated using a combination of conventional cytogenetics methods (chromosome analysis and fluorescence in situ hybridization) and new molecular, high throughput, and high data volume, genomic technologies including single nucleotide polymorphism (SNP) arrays, gene expression microarrays, comparative genomic hybridization (CGH) arrays as well as custom targeted, whole exome, and whole genome massively parallel DNA sequencing. We perform all our own bioinformatics and are actively engaged in the development of new analysis tools to better meet our needs and those of the scientific community. Drosophila melanogaster and the well-established GAL4/UAS/RNAi system are used to evaluate candidate ID genes with the use of a validated olfaction learning technique (T-Maze). Candidate genes are derived from our extensive clinical database of patients with ID that have already undergone diagnostic chromosomal microarray testing.
Cellular protein misfolding leads to the occurrence of amyloid oligomers and protein aggregates inside the cell. Protein misfolding is the cause of cellular dysfunction associated with numerous diseases such as cardiomyopthy, Huntington’s disease, Alzheimer’s disease, adult onset diabetes, cancer and others. To protect themselves against toxic stressors and concomitant protein aggregation, all cells possess highly conserved surveillance and repair mechanisms. One of the most central of these is the stress responsive transcriptional program called the ‘heat shock response’, controlled by the heat shock transcription factor 1 (HSF1). HSF1 upregulates a set of cytoprotective proteins, the so-called heat shock proteins (HSPs) which help refold and/or degrade damaged proteins to restore homeostasis. Previously, we have shown that in the animal model Caenorhabditis elegans the upregulation of HSPs upon protein misfolding is not regulated cell autonomously by the amounts of protein misfolding, but instead, is under the control of the organism’s nervous system. Our lab works on understanding how the nervous system of C. elegans controls the cellular response to stress and protein misfolding. Specifically, we use the powerful genetic techniques afforded to us by the use of C. elegans to ask:
a) What genes and signaling pathways are involved in how the nervous system detects suboptimal environmental conditions, or stressb) What signaling pathways are responsible for transmitting this information to non-neuronal cellsc) How is the accumulation of protein damage in non-neuronal cells communicated to the nervous systemd) How do these signaling mechanisms ultimately result in an adaptive, organimal response to macromolecular damage and stress.
Identifying genetic and epigenetic risk factors for suicidal behavior
The primary goal of our laboratory is to identify genetic and epigenetic risk factors for suicidal behavior. Family, twin, and adoption studies make clear that suicidal behavior has a substantial heritable component. While there is evidence that this heritability is accounted for in part by a liability to mood disorder, other evidence suggests an independent heritable facet that may cut across multiple psychiatric disorders. In an effort to better understand the biological basis of this behavior, we have conducted a genome-wide association study (GWAS) using attempted suicide as the phenotype, an effort that identified a promising association signal on 2p25 as well as candidate genes implicating the Wnt signaling pathway and excitatory neurotransmission. These findings have prompted us to launch a large-scale whole exome sequencing project, with the goal of identifying functional variants associated with suicidal behavior on 2p25 and throughout the genome. Environmental stressors, such as child abuse and early parental loss, are also known to play important roles in triggering suicidal behavior, likely through interaction with genetic vulnerability factors. With this in mind, we have begun an epigenetics project that involves assessing genome-wide methylation patterns in post-mortem brains of suicide completers and controls, with the goal of identifying differentially methylated candidate genes and regions associated with suicidal behavior.
Homeostasis is a robust form of regulation that allows a system to maintain a constant output despite external perturbations. In the nervous system, homeostasis plays a critical role in regulating neuronal and synaptic activity. Yet the molecular basis of this form of neural plasticity is generally unknown. We address this problem using the fruit fly, Drosophila melanogaster. This model allows us to combine electrophysiology with powerful genetic and pharmacological techniques. The overall goal is to define conserved signaling mechanisms that direct synapses to maintain stable properties, like excitation levels.
It is generally believed that molecules controlling the balance of excitation and inhibition within the nervous system influence many neurological diseases. Therefore, understanding synaptic homeostasis is of clinical interest. This area of research could uncover factors with relevance to the cause and progression of disorders such as epilepsy, which reflects a state of poorly controlled neural function.
My laboratory studies genetic factors that underlie or contribute to optic neuropathies - in particular glaucoma and the neurodegeneration associated with idiopathic intracranial hypertension (IIH). Data from our studies have shown that components of the complement system are synthesized in the retina in glaucoma and that activation of complement accelerates retinal ganglion cell death. In addition, variations in certain complement component genes appear to be associated with glaucoma. A second area of interest is IIH. The genetics of this condition and the cellular events that result in the degeneration of the retina are poorly understood. We are currently involved in a study designed to determine which genes are involved in the regulation of intracranial pressure and if certain genotypes are correlated with the development of the disease in human patients.
Major research interests in this laboratory concern the genetic control of function and development of the nervous system. Currently we focus on mutants of the fruit fly Drosophila with altered nerve excitability and deficiencies in learning behavior. The effects of single-gene mutations and their interactions in double mutants provide clues for the functional organizations of the ionic channels and second messenger pathways that govern neuronal activities and synaptic plasticity.Mutant alleles and conditional expression of transients are analyzed to elucidate experience-dependent plasticity in the development of the functional organization in the nervous system. The effects of altered nerve activity and physiological actions on the path finding, arborization, and generation of neural connectivities are determined in neuronal cultures as well as in genetic mosaics.
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