Neurogenetics

Ben Darbro M.D., Ph.D.

Current
Ben
Darbro
M.D., Ph.D.
Assistant Professor, Director of the Shivanand R. Patil Cytogenetics and Molecular Laboratory
Pediatrics
Research area(s): 
Genetic Determinants of Intellectual Disability
Address
Research
Research Focus: 

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.

Veena Prahlad Ph.D.

Current
Veena
Prahlad
Ph.D.
Assistant Professor
Biology
Research area(s): 
Neuronal control of cellular stress responses
Address
338
BBE
331
BBE
Research
Research Focus: 

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 stress
b)  What signaling pathways are responsible for transmitting this information to non-neuronal cells
c)  How is the accumulation of protein damage in non-neuronal cells communicated to the nervous system
d)  How do these signaling mechanisms ultimately result in an adaptive, organimal response to macromolecular damage and stress.

Virginia L. Willour Ph.D.

Current
Virginia
L.
Willour
Ph.D.
Associate Professor
Psychiatry
Research area(s): 
Human Genetics & Neurogenetics
Address
B002J
ML
B002
ML
Research
Research Focus: 

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.

Faculty affiliations: 

Bridget Lear Ph.D.

Current
Bridget
Lear
Ph.D.
Assistant Professor
Biology
Research area(s): 
Neural and genetic basis of circadian behavior
Address
446
Biology Building
450
BB
Research
Research Focus: 

My lab is interested in understanding the neural mechanisms that regulate circadian rhythms, the daily patterns of physiology and behavior that are prominent in many species.  We study the model system Drosophila, whichexhibits robust daily rhythms in several behaviors, including locomotor activity.  Genetic approaches in Drosophila have led to the identification of a number of key circadian rhythms genes, including several with conserved function in mammals.  Much of this research has focused on understanding the molecular circadian clock, the cell-autonomous transcriptional feedback loops and post-translational modifications that generate ~24 hour molecular oscillations.  In Drosophila and mammals, the central circadian clocks that control rhythmicity are located in neuronal groups within the brain. Yet, little is known about how the molecular clock regulates the output of these neurons to promote rhythmicity.  We are interested in understanding the processes that occur downstream of the molecular clock to mediate circadian neuron function. I have previously demonstrated that a putative sodium leak channel, narrow abdomen (na), is an important component of circadian neuronal output in Drosophila. We are now using this system to further characterize the function and regulation of this unique channel, with a particular interest in determining whether NA is subject to circadian regulation. In addition, my lab is utilizing the molecular and genetic tools of Drosophila in order to identify new circadian rhythms genes, with a focus on genes likely to function in circadian neuronal output.

Faculty affiliations: 

C. Andrew Frank Ph.D.

Current
C. Andrew
Frank
Ph.D.
Assistant Professor
Anatomy and Cell Biology
Research area(s): 
Homeostatic Control of Synaptic Function
Address
1-661A
Bowen Science Building
Research
Research Focus: 

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.

Faculty affiliations: 

Markus H Kuehn Ph.D.

Current
Markus
H
Kuehn
Ph.D.
Associate Professor
Ophthalmology and Visual Sciences
Research area(s): 
Genetics of Optic Neuropathies
Address
4120F
MERF
4120
MERF
Research
Research Focus: 

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.

Faculty affiliations: 

Chun-Fang Wu Ph.D.

Current
Chun-Fang
Wu
Ph.D.
Professor
Biology
Research area(s): 
Neurogenetics of Drosophila
Address
237
BB
231
BB
Research
Research Focus: 

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.

Faculty affiliations: 

John R Manak Ph.D.

Current
John
R
Manak
Ph.D.
Associate Professor
Biology
Research area(s): 
Genetic basis of human disease using high-throughput genomics methodologies, fruit fly models of human disease and cancer.
Address
459A
BB
455=9A
BB
Research
Research Focus: 

Research in my laboratory covers three different but not mutually exclusive areas: 1) high-throughput genomics technologies to identify the genetic basis of human disease, 2) fruit fly models to understand human diseases such as epilepsy and cancer, with an emphasis on chromatin structure, 3) genomic technology development to facilitate identification of important mutations in both humans and model organisms. 

For the first project, we are utilizing array-based comparative genomic hybridization (aCGH) to identify copy number variants associated with a number of diseases, including cleft lip and palate, spina bifida, and renal agenesis (all relatively common birth defects).  Using this approach, we identify genes whose copy number is altered in affected individuals, and we functionally validate these disease-associated genes in vertebrate animal models such as frogs and fish.  Additionally, we are using exome sequencing to explore the genetic basis of the aforementioned diseases.  This new genomics technology allows enrichment and high-throughput sequencing of the protein-coding exons in the human genome; since roughly 85% of the mutations causing Mendelian disorders are thought to reside in such exons, this strategy eliminates the need for costly whole-genome sequencing.  However, this type of analysis requires careful selection of pedigrees that show strong Mendelian inheritance patterns of the disease, which is turn suggest that high effect loci are at play in the disease process in these families. 

For the second project, we are studying the Drosophila homolog of the c-Myb proto-oncogene (which causes leukemia and lymphoma in birds and mammals).  In particular, we are exploring the role of Drosophila Myb (Dm-Myb) in modulating chromatin structure and controlling gene expression.  Our recent results demonstrate that the Myb protein is controlling gene expression through its interaction with other chromatin-modulating factors, and that Myb is regulating different targets in different cell types.  Most interestingly, in contrast to the dogma in the field, Myb is a potent repressor of large numbers of genes in certain specialized cell types.

Additionally, we are using the Drosophila system to model another human disease, myoclonic epilepsy.  We have shown for the first time that the same gene mutated in flies, mice and humans causes this form of epilepsy, and that the epileptic flies can be successfully treated with human anti-epileptic medications (Am J Hum Genet, 2011).  Intriguingly, the mutated gene is prickle, a gene that has been shown to be involved in establishing planar cell polarity.  A number of laboratories have worked on this gene over the course of many years with regard to its involvement in planar polarity; however, up until now the epileptic behavioral phenotype had been missed.        

For the third project, we are developing a novel mutation mapping technology (in collaboration with my colleague in the dept, Josep Comeron) in order to efficiently and cost-effectively map both human disease-causing mutations as well as mutations of interest in a variety of model organisms, including mice and flies.  Currently, our technology can correctly identify known SNPs with an accuracy of 99% and we are now using the technology to identify novel mutations in several human diseases.    

Faculty affiliations: 

Curt D Sigmund Ph.D.

Current
Curt
D
Sigmund
Ph.D.
Professor
Pharmacology
Research area(s): 
Computational Genetics; Eukaryotic Gene Expression
Address
Research
Research Focus: 

Peroxisome proliferator activated receptors (PPAR's) are ligand activated transcription factors which have a pleiotropic role in many physiological processes. PPARγ is the molecular target of the thiazolidinediones class of drugs which are used to treat patients with non-insulin dependent diabetes mellitus (NIDDM). Endothelial dysfunction, which develops in patients that are diabetic or chronically hypertensive, is thought to contribute to the progression of carotid artery disease, cerebral vascular dysfunction and stroke. PPARγ is expressed in vascular endothelium and smooth muscle and therefore is a potentially important factor in the regulation of vascular function and blood pressure. PPARγ has been reported to inhibit responses to vasoconstrictors such as endothelin, stimulate the release of vasodilators, and increase expression of CuZn-SOD in vascular muscle and endothelium. Importantly, patients carrying dominant negative mutations in PPARγ exhibit early onset type II diabetes and hypertension. Current data suggests that PPARγ exerts a protective effect in the vessel wall and we hypothesize that PPARγ plays an important role in the regulation of vascular function and blood pressure. We are currently testing this hypothesis using a variety of genetic, computational and Bioinformatic tools. We are: 1) using adenoviruses over-expressing wildtype and dominant negative mutations of PPARγ in blood vessels from normotensive and hypertensive mice to test whether they can alter endothelial function, 2) developing novel transgenic mice with expression of the wild-type and dominant negative mutants of PPARγ targeted specifically to vascular muscle and endothelial cells using cell-specific promoters, 3) using microarrays to determine the transcriptional targets of PPARγ, and 4) using computational and Bioinformatic tools to scan genomic sequences for PPARγ response elements (PPRE).

Andy F Russo Ph.D.

Current
Andy
F
Russo
Ph.D.
Professor
Molecular Physiology & Biophysics
Research area(s): 
Eukaryotic Gene Expression; Molecular and Biochemical Genetics
Address
5-432
BSB
5-433
BSB
Research
Research Focus: 

My research interest is the control of neuronal gene expression. The major focus of the lab is on the neuropeptide CGRP and its role in migraine. The role of CGRP in migraine is supported by the ability of CGRP to cause headache and the recent efficacy of a CGRP antagonist as an antimigraine drug. We have found that the CGRP gene is up-regulated by cytokine-induced MAP kinases and repressed by antimigraine drugs that appear to act via an unusually prolonged calcium signal. We are currently investigating these mechanisms using adenoviral-mediated gene transfer to cultured trigeminal neurons and intact ganglia in vivo. We are also using gene transfer and transgenic mice to regulate CGRP receptor activity in the vasculature and nervous system by overexpressing the RAMP1 subunit of the CGRP receptor. The RAMP1 transgenic mice are sensitized to CGRP-induced neurogenic inflammation. The RAMP1 transgenic mice display a unique phenotype has raised the possibility that these mice may provide a model for some aspects of migraine, which is currently being explored. In collaborative projects, we are studying the beneficial effects of CGRP against hypertension and following myocardial infarction in the RAMP1 mice. Other collaborative projects include the regulation of serotonin biosynthesis, which may be important in migraine and behavioral disorders, and use of the CGRP promoter to target a dominant negative oncogene to specific neuroendocrine cells. The overall goal of these projects is to develop effective diagnostic and therapeutic strategies.

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