Our laboratory studies transcriptional processes that are disrupted in disease. We identified a novel transcriptional signaling pathway in the heart that mediates the heart’s ability to regulate whole body metabolism. Through a combination of pharmacological and genetic gain- and loss-of-function studies in mice, we found the heart is capable of regulating whole body metabolism through a mechanism that is governed by MED13 and miR-208a. MED13 is a particularly interesting component of the Mediator complex because it functions as a molecular bridge between the core complex and kinase submodule, providing a mechanism for spatial and temporal control of Mediator-dependent regulation of transcription. In addition, we are studying the function of multiple components of Mediator including CDK8, CDK19, MED12 and CycC. We primarily utilize mutant mouse models to study the proteomic, molecular, bioinformatic and biochemical methods to study the molecular signaling events controlling cardiac response to stress.
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.
The Genetics of Eukaryotic Transcriptional Enhancers
Transcriptional enhancers are DNA sequences that specify inducible, spatiotemporal patterns of gene expression at most gene loci. Several complementary results from genomic studies have shown that the majority of functional sites in a genome correspond to transcriptional enhancer sequences, thus underscoring their importance for understanding basic physiology. However, while transcriptional enhancers represent a major class of regulatory DNAs in eukaryotic genomes, the entire set of sequences that are necessary and sufficient for constructing a complex eukaryotic enhancer are not yet known.
Our laboratory is focused on using molecular biology, genomics, bioinformatics, and transgenic model systems to understand enhancer biology. A major area of focus in our laboratory is the study of how different morphogen-concentration specific responses are encoded at different loci. We are also interested in understanding the sequence-function relationship well enough to understand the complex patterns of molecular evolution occurring at enhancer sequences.
Work in the Ellermeier Lab focuses on how Gram-positive bacteria sense and respond to extracellular signals. Our work is focused on the opportunistic human pathogen Clostridium difficile and the model organism Bacillus subtilis. We are interested in understanding how cells respond to changes in their environment by altering gene expression. To alter gene expression bacteria must detect changes in their environment and then transduce that signal from outside the cell to a transcriptional response inside the cell. We are interested in understanding the basic molecular mechanisms involved in how cells sense and respond to extracellular signals. We utilize genetic, molecular, biochemical and structural approaches to dissect these signal transduction systems.
We are particularly interested in understanding the response of C. difficile to factors produced by the innate immune system. Our work has revealed the presence of an Extra Cytoplasmic Function (ECF) σ factor, σV, present in C. difficile and B. subtilis as well as other Gram-positive bacteria that is activated specifically by lysozyme, an essential component of the innate immune system. We have found that σV is required for lysozyme resistance in both B. subtilis and C. difficile. The activity of σV is inhibited by the anti-sigma factor RsiV. Activation of σV occurs via proteolytic destruction of an anti-sigma factor RsiV. This degradation occurs only in the presence of lysozyme and requires multiple proteases to destroy RsiV in a process of regulated intramembrane proteolysis (RIP). We are interested in identifying the proteases required for σV activation and understanding the mechanism by which site-1 cleavage of RsiV, and thus σV activation, is controlled. We are also studying the role of additional ECF sigma factors encoded by C. difficile to determine their role in response to cell envelope stress. In addition, we are interested in understanding the role of these ECF sigma factors play in survival of the bacterium during an infection.
Prostaglandins are transiently acting hormones that are synthesized at their sites of action by cyclooxygenase (COX) enzymes, the targets of Aspirin and Advil, to mediate a variety of biological activities, including inflammation, sleep, reproduction, and cancer development. How do prostaglandins regulate these diverse, cellular events? To address this question we have developed Drosophila oogenesis as a new a new and powerful model for studying prostaglandin signaling. Using both pharmacology and genetics, we discovered that prostaglandins mediate Drosophila follicle development, identified the Drosophila COX1 enzyme, Pxt, and revealed that genetic perturbation of prostaglandin signaling can be used to exam the function of prostaglandins. This research on prostaglandin signaling implicates it in modulating actin/membrane dynamics, cell migration, stem cell activity, and the timing of gene expression during Drosophila follicle development. The lab is currently pursuing how prostaglandin signaling regulates actin dynamics and invasive cell migrations during Drosophila follicle development. By using a multifaceted experimental approach that combines Drosophila genetics, cell biology, live imaging, and biochemistry to we can begin to work out the mechanisms by which prostaglandins regulate these processes, and provide general insight into how prostaglandins regulate the cytoskeleton and migration at a cellular level. Such mechanisms of prostaglandin action are likely to be reutilized throughout development, including mediating the changes that occur during cancer progression and metastasis.
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).
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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