Bridget Lear Ph.D. [Former faculty]

Thomas Nickl-Jockschat M.D.

Current
Thomas
Nickl-Jockschat
M.D.
Associate Professor
Psychiatry
Research area(s): 
Neurodevelopmental psychiatric disorders
Address
Research
Research Focus: 

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.

Faculty affiliations: 

Ted Abel Ph.D.

Current
Ted
Abel
Ph.D.
Professor
Director, Iowa Neuroscience Institute Roy J. Carver Chair in Neuroscience
Research area(s): 
Molecular mechanisms of memory storage and the molecular basis of neurodevelopmental and psychiatric disorders
Address
2312
PBDB
2400
PBDB
Research
Research Focus: 

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.

Faculty affiliations: 

Aislinn Williams M.D., Ph.D.

Current
Aislinn
Williams
M.D., Ph.D.
Assistant Professor
Psychiatry - Division of Molecular Psychiatry
Address
2326
PBDB
2310 F-1
PBDB
Research
Research Focus: 

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.

 

Training Program Affiliations

Interdisciplinary Graduate Program in Neuroscience

Center, Program and Institute Affiliations

Iowa Neuroscience Institute

 
Faculty affiliations: 

Ben Darbro M.D., Ph.D.

Current
Ben
Darbro
M.D., Ph.D.
Associate 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.

Shizhong Han Ph.D.

Assistant Professor
Psychiatry

Veena Prahlad Ph.D.

Current
Veena
Prahlad
Ph.D.
Associate 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.

Assistant Professor
Biology

Joshua A. Weiner Ph.D.

Current
Joshua
A.
Weiner
Ph.D.
Professor
Biology
Research area(s): 
Molecular Mechanisms of Neuronal Differentiation and Neural Circuit Formation
Address
348
Biology Building
348
BB
Research
Research Focus: 

Molecular Mechanisms of Neuronal Differentiation and Neural Circuit Formation

 

The mammalian brain is the most complex system in all of biology. The human brain has ~100 billion neurons and perhaps 500 trillion synapses, contact sites between neurons through which information flows. The differentiation of a vast array of distinct neuronal cell types from stem cell progenitors, and their migration to form layers and clusters, is a key developmental step that can be disrupted in human disorders such as microcephaly and lissencephaly. The elaboration of dendrites and axons and their formation of specific neural circuits underlies all mature function, and dysregulation of these processes underlies a wide variety of genetic and syndromic disorders, including forms of autism spectrum disorders, Down and Fragile X Syndromes, and schizophrenia. My laboratory is focused on identifying the fundamental molecular mechanisms that control neuronal differentiation and neural circuit formation during brain development. We take a candidate approach, generating allelic series of transgenic and knockout mice and analyzing their developmental phenotypes with a wide range of genetic, biochemical, pharmacological, molecular biology, and cell biology techniques. We focus on genes and processes that have been implicated in human neurodevelopmental disorders. Multiple projects are available for ambitious graduate students, postdocs, and undergraduate Honors students. Our work has been continuously funded since the lab’s founding in 2004, including grants from the National Institutes of Health, the March of Dimes, the Carver Trust, the Nellie Ball Trust, the Mallinckrodt Foundation, the E. Matilda Ziegler Foundation for the Blind, and the National Multiple Sclerosis Society.

Protocadherins

Three large clusters of cadherin-related genes (Protocadherin-α, -β, and -γ) lie in a tandem array on a single chromosome in mammals. The γ cluster, on which we focus, consists of 22 "variable" exons, each of which encodes the extracellular, transmembrane, and partial cytoplasmic domains of a single protocadherin (Pcdh) isoform. Each variable exon is spliced to a set of three "constant" exons which encode a shared C-terminal domain. Thus, a variety of adhesive specificities can link into a common signaling pathway. Because each neuron expresses ~6 of the isoforms in a semi-stochastic manner, the γ-Pcdhs may provide a “molecular code” that helps specify cell-cell interactions. We have shown that the γ-Pcdhs act as homophilic adhesion molecules, and have identified them as critical mediators of proper dendrite arborization and synaptogenesis in the cerebral cortex. Homophilic trans-interactions between specific γ-Pcdh isoforms on neurons and astrocytes regulates the extent of dendrite outgrowth in vivo. Additionally, cis-interactions between the γ-Pcdhs and the autism-associated protein neuroligin-1 regulate the formation of dendritic spines and excitatory synapses in the cortex. Importantly, epigenetic regulation of γ-Pcdh repertoire is disrupted in neurodevelopmental disorders such as Down syndrome, indicating that the mechanisms we’ve discovered have implications for both normal and disrupted human development. In new work, we’ve used CRISPR/Cas9 genome editing to generate a new series of mice in which γ-Pcdh diversity is reduced. We will use these mice to test hypotheses about the role of molecular specificity in cell-cell interactions in vivo, and to define human disease-relevant behavioral deficits that result from altered γ-Pcdh expression.

Akirins

A key step in the development of the brain is the transition from proliferating neural progenitors to postmitotic neurons that then migrate to their final cellular position and differentiate and elaborate dendrites and axons to form circuits. The molecular mechanisms regulating neuronal differentiation are only partially understood; recent work indicates that chromatin remodeling machinery, which regulates the expression of thousands of genes by altering DNA structure, plays an important role. Akirin2 is a nuclear protein that is known to interact with subunits of the BAF chromatin remodeling complex, but whose function in mammalian cells has been obscure. We found that the Akirin2 gene is expressed in cortical progenitors and in postmitotic cortical neurons, and generated cortex-restricted knockout mice using the Cre/LoxP system to analyze the function of Akirin2. Remarkably, when Akirin2 is absent from cortical progenitors, they completely fail to generate the cerebral cortex, and exhibit an extreme form of microcephaly. Most knockout mice die at birth with little-to-no cortical tissue present; a few survive postnatally, despite lacking a cortex. Analyzing control and knockout transcriptomes using RNA sequencing suggests that Akirin2 is critical for activating genes maintaining progenitor fate, and for repressing the genes associated with neuronal differentiation. Using distinct Cre transgenic lines to limit Akirin2 mutation to astrocytes, we have also found severe defects in the cerebellum indicative of defective neuronal migration and differentiation. These data identify Akirin2 as a novel master regulator of gene expression patterns required for proper neuronal and glial cell fates.

Faculty affiliations: 

C. Andrew Frank Ph.D.

Current
C. Andrew
Frank
Ph.D.
Associate 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: 

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