A critical component of airways innate defense is the thin liquid layer lining airway surfaces, the periciliary liquid (PCL), that provides a low viscosity solution for ciliary beating and acts a lubricant layer for mucus transport. Normal airways appear to be able to sense the PCL volume and adjust ion channel activity accordingly. The long term goal of this laboratory is to understand how homeostasis of PCL volume occurs in airway epithelia under normal and pathophysiological conditions. Currently, research in the Tarran lab is focused on three main areas: 1) Regulation of epithelial cell function by the extracellular environment, 2) Gender differences in cystic fibrosis lung disease and 3) The effects of cigarette smoke on epithelial airway ion transport. We utilize cell biological and biochemical techniques coupled with in vivo translational approaches to address these questions.
The goal of our research is to identify signaling mechanisms that contribute to normal and pathophysiological cell growth in the cardiovascular system. We study cardiac and vascular development as well as heart failure and atherosclerosis.
The Cancer Biology Group at NIEHS focuses on early events in skin tumor development using a transgenic mouse model (TgAC). This model possesses a v-Ha-ras transgene under the regulation of a fetal globin promotor integrated at an ectopic site which confers a unique phenotype of inducible skin papillomas with a high rate of progression to invasive squamous and spindle cell neoplasms. The goals of our studies are to identify and characterize: 1) The cellular origin of the tumors and 2) critical genes which are involved in ras-mediated tumor induction and progression. Conventional cancer therapies have until recently depended on treatment late stages of tumor growth and involved non-specific mechanisms of cellular injury. By focusing on understanding early events in tumor induction we hope to gain insights into targets for intervention that can more specifically inhibit cancer cell growth.
My primary research interests are directed at the neurobiology of alcoholism. To study the central mechanisms involved with neurobiological responses to ethanol, I use both genetic and pharmacological manipulations. There are many factors that may cause an individual to progress from a moderate or social drinker to an alcoholic. In addition to environmental influences, there is growing evidence in both the human and animal literature that genetic factors contribute to alcohol abuse. Furthermore, the risk for developing alcoholism is likely not associated with a single gene, but rather with multiple genes that interact with environmental factors to determine susceptibility for uncontrolled drinking. Some of the questions that my laboratory is currently addressing are: 1) Does central neuropeptide Y (NPY) signaling modulate neurobiological responses to ethanol and ethanol consumption, 2) Do melanocortin peptides modulate ethanol intake? and 3) Does cAMP-dependent kinase (PKA) play a role in voluntary ethanol consumption and/or other effects produced by ethanol?
The immune system is a network of interacting biological cells. The molecular events that lead to the activation and regulation of these cells often occur at the cell surface. However, little is known about the arrangement, motions and interactions of the participating cell-surface molecules. To examine these phenomena, we construct model cell membranes on planar supports from purified or synthesized molecules. Recently developed techniques in laser-based fluorescence microscopy can then be employed to examine the behavior of select fluorescently labeled molecules at or near the supported planar membranes. This research is significant not only in the basic understanding of the immune system, but also in other areas of cell-cell communication and cell membrane biophysics, in the physics of two-dimensional fluids, and in biotechnology.
Our laboratory uses the mouse as a model to study phenotypes with complex etiologies contributed by genetic and environmental factors and that underlie differences in susceptibility to common diseases. Genetics and a broad range of genomic, bioinformatic and computational tools are used in a new integrative field called systems genetics. Through many collaborative interactions, major research foci are currently in development, reproduction, neurobiology, cancer (colon and breast), cardiology, exposure biology and computational genetics. Our laboratory is also investigating the function role of the Egfr/Erbb gene family of receptor tyrosine kinases through embryonic stem cell manipulation, transgenics, gene targeting and other genetic engineering technologies.
Dr. Tidwell's research is focused on the design and synthesis of new drugs for the treatment of AIDS-associated opportunistic infections. The rationale for design of new drugs is directed at determining the mechanisms of action, antimicrobial activity, and pharmacokinetics of dicationic molecules. Studies have been initiated to isolate and identify new drug targets from Pneumocystis carinii and Cryptosporidium parvum utilizing molecular modeling and biochemical methods to aid in the determination of new structures. The role of proteases and imidazoline receptors in the pathogenesis of disease continues to be a major area of research as well as a new prodrug approach for the cationic molecules to allow for much improved bioavailability.
Biophysics of cortical information processing, selective attention in the mammalian visual pathway and evidence for spike patterns in cortical spike trains
Topics include gene discovery, genomics/proteomics, gene transcription, signal transduction, molecular immunology. Disease relevant issues include infectious diseases, autoimmune and demyelinating disorders, cancer chemotherapy, gene linkage.
Projects involve the study of cellular and molecular events involved in autoimmunity, and development and application of genetic vaccines to prevent and treat autoimmunity and cancer.
The major area of our research is Biomolecular Informatics, which implies understanding relationships between molecular structures (organic or macromolecular) and their properties (activity or function). We are interested in building validated and predictive quantitative models that relate molecular structure and its biological function using statistical and machine learning approaches. We exploit these models to make verifiable predictions about putative function of untested molecules.
Blood Flow and Endothelial Cell Function. We are interested in how vascular endothelial cells signal and respond to blood flow in the context of cardiovascular disease and tumor progression.
