Affiliated Faculty
Joseph Angleson
Associate Professor, Department of Biological Sciences
Cellular endocrinology: processes related to diabetes and endocrine disorders.
The endocrine system is comprised of a set of small organs or glands that all are involved in the release of specific hormones into circulation. This system is essential to the regulation of diverse, critical, body functions such as metabolism, growth, development and reproduction and the stress response. Our primary focus is on the endocrine cells that are required to maintain healthy blood sugar levels.
Studies of the endocrine cells of islets of Langerhans in the pancreas are of central importance for both our understanding of the cause of diabetes and potential treatments and cure. Diabetes is a disease in which the body fails to properly maintain healthy levels of the simple sugar, glucose, in the blood. Regulation of blood glucose levels is the job of the hormone producing alpha and beta cells in the pancreas. Alpha cells release the hormone glucagon when blood glucose is too low and beta cells release the hormone insulin when blood glucose is high. We study the fundamental cellular and molecular mechanisms that regulate hormone secretion from these two cell types.
The lab also studies mechanisms of signaling and secretion responsible for hormone release from the anterior pituitary gland. This includes studies related to secretion of prolactin, growth hormone, the reproductive hormones FSH & LH, and the stress hormone ACTH. All projects use a combination of cell biology, molecular biology and biophysical techniques. We use a variety of imaging technologies including digital-deconvolution, particle tracking, laser scanning confocal microscopy for FRAP and FRET of fluorescent protein-based probes and ratiometric imaging of intracellular ion concentration.
Patrick Bosque
Visiting Scholar, Eleanor Roosevelt Institute
Protein Misfolding and Amyotrophic Lateral Sclerosis (Lou Gehrig’s Disease)
Dr. Bosque is investigating the role of misfolded and aggregated proteins in amyotrophic lateral sclerosis (ALS), also called Lou Gehrig’s disease. ALS is a fatal disease that causes progressive weakness by killing off motor neurons. The root cause of ALS is unknown. Microscopic examination of the spinal cord and brain of people who die of ALS shows signs of some protein building up in misfolded and abnormally aggregated form. This misfolded protein may be the cause of ALS and the goal of Dr. Bosque’s investigations is to identify the protein and why it misfolds. Current investigations are pursuing the possibility that this protein may misfold in a manner analogous that of the prion protein, which causes Creutzfeldt-Jakob disease, mad cow disease and other conditions. The peculiar property of the prion protein is that it can be triggered to misfold by the presence of already misfolded prion protein, so that misfolding can propagate almost like an infection. A goal is to exploit this hypothetical property of the protein causing ALS to identify it and its mechanism of misfolding.
Christina Coughlan
Assistant Professor, Department of Biological Sciences
Alzheimer’s disease and Dementia in Diabetes
Alzheimer’s disease (AD) is a neurodegenerative disorder that leads to memory loss and death of all patients affected. Only 5% of AD cases are genetic leaving 95% of AD cases as having no fully understood cause (sporadic). Regardless of the origin, genetic or sporadic, all patients with AD have an increased production of amyloidogenic fragments in their brains. These fragments are formed from a protein known as Amyloid Precursor Protein (APP).
APP is a protein that is found in every cell in our body. Although its function as a full-length protein is poorly understood, we do know that fragments of APP play a central role in the development of AD. Abeta is a peptide fragment derived from APP that has many toxic functions any or all of which may lead to the death of brain cells that cause AD. Given the toxic role of this peptide much research has focused on trying to understand why and how Abeta peptide reaches such high levels in our cells and in our brains. We hypothesize that the removal of the activity of a hormone known as leptin is one of the factors that is to blame. Another is the loss of cell functions that normally remove toxic proteins and protect cells.
Leptin is a hormone released from fatty tissue which is involved in suppressing appetite and in modulating fat deposition and brain and nerve cell development. In the absence of leptin Abeta peptide deposition is favored and so more toxic peptide is found in brain cells. Interestingly, aging and obesity are risk factors for the development of AD and insensitivity to leptin is known to develop as we age or become obese. Thus by either aging or becoming obese, the effects of leptin are removed and the risk of AD increases. We hypothesize that these connections are more than just coincidence. We are thus interested in understanding the effect(s) of leptin deficiency and how it acts as a risk factor for the development of AD. We are also working on projects to help us understand the parts of the cell that are important for generating Abeta peptide and, in collaboration with Dr. Shaheen, designing therapeutic approaches to remove this toxic peptide once it is made.
Phillip Danielson
Professor, Department of Biological Sciences
Amyotrophic Lateral Sclerosis "Lou Gehrig's Disease"
Dr. Phillip B. Danielson has recently joined the ERI research team studying amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease. ALS is known to have both sporadic and familial forms. Mutations in the copper-zinc superoxide dismutase gene (SOD1) account for 10 to 20 percent of the inherited ALS. Over 100 different mutations in the SOD1 gene can cause ALS in humans and at least 8 of these have been shown to produce an ALS-like phenotype when expressed in transgenic mice. Dr. Kunst previously found that one of these mutants (murine G86R (mG86R) SOD1) is highly dependent upon the strain background. Depending on the background, onset of ALS due to this SOD1 mutation can vary from an average of 103 days to 211 days. Dr. Kunst and her research group have isolated several modifier genes, which reflect the differences in the genetic background of certain mouse strains and are characterizing their genetic location, expression, and impact on ALS onset. Identification of modifier genes and characterization and their mechanism(s) of action may lead to as yet unidentified targets of pharmacological intervention for ALS.
Dr. Danielson teaches courses in, Virology / Infectious Human Disease, Immunology, Human Molecular Biology and Forensic Biology. His research program encompasses studies in forensic genetics and comparative proteomics - particularly the development of new technologies for the analysis of DNA mixtures.
Dr. Danielson has worked in collaboration with forensic scientists from around the world. His work has been featured in both academic and professional journals and magazines including the Proceedings of the National Academy of Sciences, The Scientist magazine, USA Today and Law Enforcement Technology magazine. He also serves a science advisor to the National Law Enforcement and Corrections Technology Center for the Rocky Mountain Region.
James Fogleman
Professor, Department of Biological Sciences
Amyotrophic Lateral Sclerosis, “Lou Gehrig’s Disease”
Dr. Fogleman has recently joined the ERI’s research program focusing on ALS (amyotrophic lateral sclerosis or Lou Gehrig's disease), a fatal neurodegenerative disease characterized by progressive paralysis. Dr. Cathy Kunst is a collaborator on this project which is housed in the Eleanor Roosevelt Institute at the University of Denver.
ALS is known to have both sporadic and familial forms. Mutations in the copper-zinc superoxide dismutase gene (SOD1) account for 10 to 20 percent of the inherited ALS. Over 100 different mutations in the SOD1 gene can cause ALS in humans and at least 8 of these have been shown to produce an ALS-like phenotype when expressed in transgenic mice. Dr. Kunst previously found that one of these mutants (murine G86R SOD1) is highly dependent upon the strain background. Depending on the background, onset of ALS due to this SOD1 mutation can vary from an average of 103 days to 211 days. Dr. Kunst and her research group have isolated several modifier genes, which reflect the differences in the genetic background of certain mouse strains and are characterizing their genetic location, expression, and impact on ALS onset. Identification of modifier genes and characterization and their mechanism(s) of action may lead to as yet unidentified targets of pharmacological intervention for ALS.
Catherine Kunst
Research Professor, Eleanor Roosevelt Institute
Amyotrophic Lateral Sclerosis "Lou Gehrig's Disease"
Dr. Kunst's research focuses on ALS (amyotrophic lateral sclerosis or Lou Gehrig's Disease), a fatal neurodegenerative disease characterized by progressive paralysis. Dr. Kunst discovered that certain genetic variations in the mouse that can prevent ALS in mice otherwise destined to die from the disease. She is currently working to identify these protective genes and what they do in the hope that this discovery will lead to medicines that mimic the effect of the protective genes for treating ALS in people.
Daniel Linseman
Assistant Professor, Department of Biological Sciences
Unraveling the Role of Cell Death in Neurodegeneration
The principal research focus of Dr. Linseman’s laboratory is to elucidate the molecular mechanisms by which neurons die in various neurodegenerative disorders. A major emphasis is to understand the role of mitochondrial oxidative stress and intrinsic apoptosis (programmed cell death) in neurodegeneration. Specific projects that are currently ongoing in the laboratory include: 1) identification of novel pathways by which pro-survival Bcl-2 proteins (eg., Bcl-2 and Mcl-1) protect neurons from mitochondrial oxidative stress and apoptosis, 2) determination of the mechanisms by which pro-death Bcl-2 proteins (eg., Bim and Puma) trigger mitochondrial oxidative stress and apoptosis, and 3) evaluation of natural product polyphenolic antioxidants (eg., green tea EGCG and red grape resveratrol) for their neuroprotective effects against mitochondrial oxidative stress and neuronal apoptosis. The laboratory routinely utilizes primary cultures of neurons obtained from rat cerebellum as an in vitro model to investigate neuronal apoptosis. The laboratory also employs mouse models of Parkinson’s disease and amyotrophic lateral sclerosis to study neuronal apoptosis in vivo. Ultimately, Dr. Linseman hopes to identify novel regulators of mitochondrial oxidative stress and intrinsic apoptosis that can be targeted to limit neuronal loss and slow the progression of various neurodegenerative diseases.
Nancy Lorenzon
Assistant Professor, Department of Biological Sciences
Human diseases resulting from altered calcium signaling in muscle and neurons
My research focuses on acquiring a better understanding of calcium channel function and protein interactions involved in calcium signaling in muscle and neurons. Calcium serves as a second messenger in many cellular functions throughout the nervous system and in skeletal and cardiac muscle. As a result of the diverse roles of calcium ions in cellular function, genetic mutations in calcium channels can affect not only the electrical activity of cells but also diverse downstream signaling. Mutations of genes encoding calcium have been implicated in the etiology of a diverse group of nerve and muscle diseases.
Calcium channel defects are responsible for inherited human disorders of skeletal muscle (including hypokalemic periodic paralysis, malignant hyperthermia and central core disease), and of cardiac muscle (arrhythmogenic right ventricular cardiomyopathy type-2 and familial polymorphic ventricular tachycardia). Neuronal calcium channels have been associated with several dominantly-inherited human diseases ranging from visual disorders to migraines, ataxia, and seizures such as familial hemiplegic migraine, cerebellar ataxia-2, congenital night blindness, generalized epilepsy, and absence seizures.
The information gained through these functional studies will be critical not only for understanding an essential function in muscular and nervous systems, but also for determining how mutational alterations of calcium channels lead to human disease, and for developing therapeutic approaches for these diseases. Research in my lab incorporates a multi-faceted approach combining electrophysiology, confocal microscopy, calcium imaging and molecular biology.
Martin Margittai
Assistant Professor, Department of Chemistry and Biochemistry
Toward a Molecular Understanding of Tau-Mediated Neurodegeneration
A common feature of more than 20 neurodegenerative diseases including Alzheimer’s disease, frontotemporal dementia, and progressive supranuclear palsy is the accumulation of pathological, amyloid-like, aggregates of the protein tau. The formation of these aggregates is a multi-step process that starts from unfolded individual tau molecules, progresses through intermediates containing several copies of tau, and ends in highly ordered, elongated, and unbranched filaments. Molecular dissection and structural characterization of this pathway has encountered great difficulties, because of the size and complexity of the involved aggregates. High-resolution methods such as X-ray crystallography and solution NMR spectroscopy that have proved unwaveringly successful in revealing the structures of soluble proteins have, until now, encountered insurmountable technical challenges.
We have sought alternative strategies to obtain structural information on the different forms of tau in the aggregation process. One strategy that has proved very successful is the labeling of tau with a small reporter molecule that allows us to follow the structural changes using a technique called electron paramagnetic resonance spectroscopy. This method faithfully delivers structural detail regardless of the size and shape of the investigated species. Using this novel approach in combination with other biophysical techniques we have gained first insights into the fine structure of tau filaments. A major goal of our lab is to extend these investigations in order to obtain a complete three-dimensional model of the tau filament. Similarly, we are analyzing the structures of tau intermediates and tau monomers and are assessing the effects individual species have on cell viability. A molecular understanding of the folding properties of tau, its cellular interactions, and structural transitions along the path from the single subunit to the complex filament will be an important prerequisite for the design of new drugs that intervene in the assembly process.
David Patterson
Professor, Department of Biological Sciences
Biochemical Genetics and Metabolomics of Human Genetic Disorders, Cancer, and Alzheimer’s Disease
Dr. Patterson’s research focuses on several medical problems:
DOWN SYNDROME and ALZHEIMER’S DISEASE
Dr. Patterson’s laboratory studies the intellectual and other disabilities faced by individuals with Down syndrome. Dr. Patterson is internationally recognized as one of the foremost authorities on Down syndrome. Current projects include analysis of alterations in brain proteins and metabolism in mouse models of Down syndrome. These studies are aimed at developing therapies to alleviate the intellectual and other disabilities seen in Down syndrome. Individuals with Down syndrome have an increased risk of developing Alzheimer’s disease at a relatively early age, and the Ts65Dn mouse model also has brain changes and learning and memory changes that resemble those seen in individuals with Alzheimer’s disease, so these studies may illuminate the disease process of Alzheimer’s disease as well.
CANCER RESEARCH
Interestingly, individual with Down syndrome have a decreased risk of developing certain cancers, including breast cancer. The Patterson laboratory has identified a gene present in an extra copy in individuals with Down syndrome that may play a role in this reduced risk and is currently developing mouse models to study this observation. Again, these studies may illuminate the process of breast cancer development and progression in individuals without Down syndrome as well and may lead to new ideas for treatment of breast cancer.
AUTISM
Dr. Patterson’s laboratory is also creating a mouse model of an untreatable inborn error of metabolism that causes profound developmental delay often accompanied by autistic features in humans. The laboratory has made significant progress in this effort, including identification of new forms of the disorder in humans. These studies include detailed analysis of changes in brain chemistry associated with this condition and studies to understand how these may be reversed.
FOLIC ACID, CANCER and DOWN SYNDROME
The Patterson laboratory has initiated studies to determine whether folic acid and homocysteine metabolism may be altered in Down syndrome and whether changes for folic acid metabolism can lead to intellectual disability and alterations in susceptibility to cancer and other disorders. Folic acid is a B vitamin that humans cannot make, so it must be acquired from the diet. Supplementation of wheat products with folic acid is currently required in the United States because it reduces the frequency of serious birth defects that affect the nervous system such as spina bifida. However, recent epidemiological evidence raises the possibility that, in older individuals, folic acid supplementation may increase the risk of breast, colorectal, and prostate cancer. Thus, this research may have significant public health implications.
Sean Shaheen
Assistant Professor, Department of Physics and Astronomy
Protein-Protein Interactions
Dr. Shaheen’s background is largely in the field of organic photovoltaic device physics and engineering. As an affiliate of ERI, he brings his knowledge of the interactions between organic molecules to bear on problems in the biological sciences. He is interested in biophysics both at the molecular and systems levels. Through collaborations with other ERI members, he is currently studying protein-protein interactions involved in pathways leading to diseases such as autism and Alzheimer's. One current project is to study how nanoparticles introduced into a protein’s environment can alter its reaction kinetics. He is also interested in using bioinformatics and protein data mining to uncover correlations in protein sequences that may reveal a protein’s phenotypic function. In general, he is interested in understanding the dynamics and rich behaviors possible in complex biological systems such as protein interaction networks and neuronal networks.
Lynn Taussig
Special Advisor to the Provost for Life Sciences, Eleanor Roosevelt Institute
Dr. Taussig, a pediatric pulmonologist, retired in 2006 as President and CEO of National Jewish Medical and Research Center, the nation’s leading institution for respiratory illnesses. Following his retirement from National Jewish, Dr. Taussig joined DU to assist in the growth of the Life Sciences program, implementation of the Molecular Life Sciences and Biophysics Programs and integration of ERI into DU and the life sciences initiatives. Prior to coming to National Jewish and DU, he was Professor and Chair, Department of Pediatrics and Director, Steele Children’s Research Center at the University of Arizona Health Sciences Center. He is the author of more that 170 publications, 4 books and numerous chapters and monographs related to respiratory illnesses in children and the recipient of numerous honors including the Alumni Achievement Award from Washington University School of Medicine and the Distinguished Achievement Award from the American Thoracic Society.
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