Dr. Macdonald is the Founder and Scientific Director of the new Metabolomic Facility and Co-Scientific Director of the joint UNC/NCSU/NOAA Marine MRI facility at Pivers Island near Beaufort NC. Dr. Macdonald's research goal is to combine metabolomics and tissue engineering and apply these tools to quantitative biosystem analysis.
My research goals are to identify the mechanisms by which environmental factors regulate smooth muscle cell phenotype and to define the transcriptional pathways that regulate SMC-specific gene expression.
Research description: Exposure to ambient air particulate matter(PM) has been associated with increased human deaths and cardiopulmonary morbidity, such as lung infections and increased asthma symptoms. I am investigating some types of PM and associated gases (such as aldehydes) that may be associated with those health effects so that the US EPA may be able to better regulate or manage the sources of the PM which are identified as playing a role in the adverse health outcomes. I am currently focusing on the effects of diesel exhaust using a variety of approaches ranging from exposing cultured human cells to the exhaust, to studying responses of humans exposed out in traffic. The EPA rules for diesel exhaust from large trucks to be implemented in 2007 and 2010 will drastically change the type of emissions, and I am currently designing and implementing testing strategies to assess the toxicity of the future types of diesel emissions. Additionally some of my research effort attempts to identify what populations are more sensitive to the effects of air pollutants, and the genetic and environmental reasons behind the increased sensitivity.
Our research is focused on the genetics and molecular pathology of complex multi-factorial conditions in humans - obesity, diabetes, hypercholesterolemia, insulin resistance, and hypertension. These conditions underlie cardiovascular diseases, including atherosclerosis, the major cause of death and disabilities in North America. Our approach consists of experiments with mice carrying modifications in various genes important for the maintenance of vascular function, antioxidant defense, and metabolism. We dissect how gene-gene and gene-environment interaction influences the pathogenesis of these common human conditions and their
complications.
The Magnuson Lab works in three areas - (i) Novel approaches to allelic series of genomic modifications in mammals, (ii)Mammalian polycomb-group complexes and development, (iii) Mammalian Swi/Snf chromatin remodeling complexes
Dr. Maixner’s research program focuses on identifying the pathophysiological processes that underlie pain perception, persistent pain conditions, and related disorders. His current research focuses on genetic, environmental, biological, and psychological risk factors that contribute to the onset and maintenance of chronic pain conditions. A long term goal of his program is to translate new discoveries into clinical practices that improve the ability to diagnose and treat patients experiencing chronic pain.
We study genetic controls of vascular development in mouse and chick models. Current projects focus on the roles of sonic hedgehog and transcriptional silencers in control of vascular stem and progenitor cell differentiation. Other ongoing projects examine the role of notch signaling in coronary artery development, and explore the link between cytoskeletal remodeling and transcriptional activation in smooth muscle differentiation.
Physiology and pharmacology of the basal ganglia; neurobiology of motivation and reward; substance abuse neurobiology; and neurobehavioral teratology.
My laboratory studies the function of neural circuitry involved in the perception of reward and the reinforcement of motivated behaviors in several mouse models of neurodevelopmental disorders, including early developmental exposure to drugs of abuse, such as alcohol or cocaine; and genetic models relevant to the study of autism, such as inactivation of the Fmr1 (Fragile-X Mental Retardation) or MeCP2 (Methyl-CpG Binding Protein) genes. My laboratory employs techniques in behavioral pharmacology, including intracranial self-stimulation (ICSS); in vitro patch-clamp electrophysiology in acute brain slices; and immunohistochemistry with unbiased stereological microscopy.
Our interest lies in the understanding of mechanisms involved in adaptation and restitution of function of striated muscle during development, injury and disease states. Regeneration of striated muscle including cardiac tissue and skeletal muscle is being actively sought with the use of various types of stem cells from various origin. We are investigating the mechanisms that control adult-derived stem cells to aquire a cardiac phenotype.
My research focuses on molecular mechanisms of mammalian nervous system development. We investigate mechanisms by which developing neurons migrate to the neocortex and form connections.
Our laboratory studies the mechanisms of sensory information processing in the nervous system, with an emphasis on processing in the auditory pathways. We study the role of ion channels in integration at the single cell level, short and long-term synaptic plasticity, synaptic function, and ion channel dynamics in the auditory brainstem and auditory cortex. We are also studying how different kinds of hearing loss affect central auditory function. Experimentally, we use patch clamp (current, voltage and dynamic clamp) methods in brain slices, live optical imaging of activity, a variety of biochemical and molecular methods, mice with genetic hearing loss, noise-induced hearing loss, auditory brainstem evoked response, and acoustic startle response to evaluate hearing function in animal models. The laboratory extensively utilizes quantitative experimental techniques, complemented with detailed computational modeling at the single cell and network levels to further understand the normal information processing capacity of auditory neurons, and the consequences of changes in ion channel and synaptic function after hearing loss.
The overall goal of our laboratory is to obtain new insights into the host-virus interaction, particularly in HIV infection, and translate discoveries in molecular biology and virology to the clinic to aid in the treatment of HIV infection. A subpopulation of HIV-infected lymphocytes is able to avoid viral or immune cytolysis and return to the resting state. Current work focuses on the molecular mechanisms that control the latent reservoir of HIV infection within resting T cells. We have found that cellular transcription factors widely distributed in lymphocytes can remodel chromatin and maintain quiescence of the HIV genome in resting CD4+ lymphocytes. These studies give insight into the basic molecular mechanisms of eukaryotic gene expression, as well as new therapeutic approaches for HIV infection.
My research interests focus on molecular events involved in the initiation of autoimmune response in multiple sclerosis (MS) and mechanisms of action of immunomodulatory and neuroprotective therapies for this disabling disease.
We are interested in the mechanisms by which histone protein synthesis is coupled to DNA replication, both in mammalian cell cycle and during early embryogenesis in Drosophila, Xenopus and sea urchins.
Protein-derived radicals, in vivo detection of free radical generation, biomarkers of oxidative stress and free radical formation in aids-related infection (Pseudomonas aeruginosa)
Research in our laboratory falls at the interface between Genetics and Cell Biology and is concentrated on understanding the molecular details of how small nuclear ribonucleoprotein (snRNP) complexes are assembled and transported to their proper subcellular compartments. Interestingly, defects in the machinery required for assembly of snRNPs are associated with a neurogenetic disease called Spinal Muscular Atrophy (SMA). Mutations in the human survival of motor neurons 1 (SMN1) gene cause SMA. A variety of projects in the lab are focused on SMN's role in the biogenesis of small RNPs as well as in neuromuscular development and function. Other projects focus on nucleocytoplasmic trafficking and the functional organization of the nucleus. We use a combination of approaches, from in vitro biochemistry and cell culture, to in vivo mouse and Drosophila model systems.
Research in our laboratory is focused on the enzymatic mechanisms and biological roles of DNA helicases. These enzymes provide the primary mechanism by which duplex DNA is converted to single-stranded DNA (ssDNA) for use as a template in DNA replication and repair or as a substrate in recombination. Indeed, these enzymes are essential for DNA replication, repair and to maintain genomic stability in all organisms. Consistent with this idea, defects in genes encoding DNA helicases in human cells have been linked to genomic instability leading to a variety of progeriod disorders and human cancers. The bacterium E. coli and the budding yeast S. cerevisiae provide attractive systems in which to pursue these studies due to the ease of genetic manipulation and the ability to isolate enzymes for biochemical studies. The long-range goal of the research program is to understand, in enzymatic and molecular terms, the mechanism of action of several helicase enzymes, and to define their individual roles in DNA metabolism.
The lab also has an interest in the process of DNA transfer by bacterial conjugation, first observed more than 50 years ago as the unidirectional and horizontal transmission of genetic information from one E. coli cell to another. Today we know that conjugative DNA transfer plays a role in increasing genetic diversity in addition to propagating the spread of antibiotic resistance and microbial virulence factors. Recent work in this laboratory and others has provided a working model of DNA transfer in the F plasmid system. The long-range goal of this research program is to define the function and regulation of the relaxosome, and each protein in this nucleoprotein complex, in conjugative DNA transfer. Based on that information we will begin to establish inhibitors of relaxosome function.
Our laboratory is interested primarily in the responses of macrophages during injury to the central nervous system and during inflammation after insult by bacterial pathogens. We use molecular, cellular and biochemical approaches both in vitro and in vivo to identify the function of key mediators during pathogenesis.
There are two ongoing projects in my lab - mechanism of binding of bacteria to plant surfaces and mechanism of carbohydrate synthesis in bacteria. We are studying the mechanisms of adhesion of the plant pathogenic and symbiotic bacteria Agrobacterium and Rhizobium to plant hosts. This binding involves protein adhesins, pilus adhesins, and carbohydrates. We are also studying the mechanisms of adhesion of the human pathogens E. coli O157 and Salmonella enterica to plant surfaces. The presence of human pathogens on produce and ready to eat fresh food has emerged as a serious concern worldwide. These bacteria bind tightly to the plant surface and can not be removed by washing. Understanding how these bacteria bind to plants is critical to preventing or inhibiting their binding and thus reducing their transmission via this route.
The second project in my laboratory concerns the mechanism of biosynthesis of polysaccharides by bacteria. We are particularly interested in cellulose and curdlan which are synthesized from the same precursor using similar proteins. We would like to understand the differences between these proteins which cause one to catalyze the synthesis of cellulose and the other to catalyze the synthesis of curdlan. We are also interested in the regulation of the biosynthesis of these exopolysaccharides, particularly in the role of cyclic diguanylic acid in this regulation.
Dr. Meeker’s research is focused on the mechanisms of HIV neuropathogenesis. Inflammatory changes within the brain caused by the viral infection initiate a toxic cascade that disrupts normal neural function and can eventually lead to neuronal death. To explore the mechanisms responsible for this damage, we investigate changes in calcium homeostasis, glutamate receptor function and inflammatory responses in primary neuronal, microglial and macrophage cultures. New therapeutic approaches targeted to signal transduction pathways and calcium regulation that protect the neurons and reduce inflammation are under investigation.
The goal of the laboratory’s research is to define the structure and function of an intracellular Ca2+ release channel in skeletal and cardiac muscle, using molecular biological and electrophysiological methods and by creating mutant mice.
Dr. Meshnick studies the molecular epidemiology of malaria and HIV, especially in pregnant women through collaborations in Malawi, the Democratic Republic of the Congo, Thailand and Cambodia. His group is also developing and using novel molecular assays to study the epidemiology and clinical significance of antimalarial drug resistance and to understand the mechanisms of action of antimalarial drugs. His group is also interested in understanding the mechanism of HIV transmission from mother to child and identifying risk factors. Currently, he is using whole genome analyses to further dissect risk factors for transmission.
My laboratory studies diffuse gliomas, devastating primary tumors of the central nervous system for which few effective drugs are currently available. We utilize model systems (genetically engineered mice, cultured cells, and human tumor specimens) to explore the molecular pathogenesis of
and develop drugs and diagnostic markers for individualized therapy of gliomas. Rotating students gain experience with techniques that include genomics (expression microarrays and array CGH), fluorescence microscopy, computer-enhanced image analysis, and tissue microarrays.
Molecular genetic analysis of virulence of Yersinia and Klebsiella: My laboratory uses Yersinia enterocolitica, Y. pestis, and Klebsiella as model systems to study bacterial pathogenesis. The long-term goals of our work are to understand the bacteria-host interaction at the molecular level to learn how this interaction affects the pathogenesis of infections and to understand how these pathogens co-ordinate the expression of virulence determinants during an infection. To do this we use genetic, molecular and immunological approaches in conjunction with the mouse model of infection. [Note: I will be moving my laboratory to UNC-CH in the summer of 2008]
Miller's research group focuses on topics in integrative biophysics:
physics applied to biology at the level of cells to organisms. In
particular, the group is interested in the role of fluid forces during
locomotion and morphogenesis. One ongoing project is focused on
understanding the aerodynamics of flight in the smallest insects.
Another current project investigates the role of fluid forces during
the development of the embryonic vertebrate heart.
Dr. Millikan's research interests include the role of genetics in human cancer, including the study of how inherited variation in DNA repair interacts with environmental factors in breast cancer, colon cancer, and malignant melanoma. He is also interested in carcinogen metabolism, and identifying causes of breast cancer in young women and African American women.
My work focuses on the role of plant pathogens in (A) controlling or facilitating biological invasions by plants, (B) structuring plant communities, and (C) modulating the effects of global change on terrestrial ecosystems. My group works on viruses, bacteria, and fungi that infect wild plants, chiefly grasses and other herbaceous species. Ultimately, I am interested in the implications of these processes for the sustainable provisioning of ecosystem services and for the conservation of biological diversity.
We are identifying genetic variants that influence common human traits with complex inheritance patterns, and we seek to understand the biological function of the identified variants. Currently we are investigating susceptibility to type 2 diabetes and obesity, as well as variation in cholesterol levels, blood pressure, body size, weight gain and early growth. In addition to examining the primary effects of genes, the lab is exploring the interaction of genes with environmental risk factors in disease pathogenesis. Approaches include genome-wide association studies, genetic epidemiology, resequencing, bioinformatic analysis, molecular biology, cell biology, and mouse models to compare high- and low-risk alleles in a whole-animal setting.
Function, expression and trafficking GABA-A receptors in the CNS; effects of chronic ethanol exposure that leads to ethanol tolerance and dependence; role of endogenous neurosteroids on ethanol action and adaptations; etiology of essential tremor.
