Cellular & Molecular Medicine

Research Interests Our objective is to define how integrin interactions within the tumor microenvironment impact prostate cancer development, hormonal resistance, and metastasis. Our approach is to understand the normal biology of the prostate gland and its microenvironment, as well as the bone environment, to inform on the mechanisms by which tumor cells remodel and use that environment to develop, acquire hormonal resistance, and metastasize. Our research is focused in three primary areas: 1) developing in vitro and in vivo models that recapitulate human disease based on clinical pathology, 2) identifying signal transduction pathway components that could serve as both clinical markers and therapeutic targets, and 3) defining the genetic/epigenetic programming involved in prostate cancer development.

Lonnie Lybarger, PhD, is an Associate Professor in the Department of Cellular and Molecular Medicine within the College of Medicine at the University of Arizona. Dr. Lybarger’s research program focuses on the mechanisms that regulate the activation of immune responses. In particular, his group studies a process known as antigen presentation, which is central to many aspects of the immune response against pathogens and tumors. This work includes detailed analyses of the cell biology of antigen presentation, as well as the study of its impact on immune responses. Recently, Dr. Lybarger has begun to study the critical link between antigen presentation and the regulation of metabolic homeostasis, with relevance to conditions such as type II diabetes.Research in the Lybarger lab has been funded by grants from State and National agencies. He has been an author/co-author on ≈35 original research reports, with his major contributions coming in the field of antigen presentation. Many of these reports involve collaborations within the University of Arizona and with colleagues at other institutions. Dr. Lybarger has served as a reviewer for University and National granting agencies, as well as reviewing for many research journals. In addition, Dr. Lybarger has served as a primary research advisor to a number of graduate and undergraduate students, while contributing to the classroom instruction of medical and graduate students.

Dr. Ledford’s current work in the area of pulmonary surfactant immunobiology combines her knowledge of mouse genetics, pulmonary disease models and immune function regulation and focuses on understanding the role of Surfactant Protein-A (SP-A) and how it regulates signaling pathways within various immune cell populations. Specifically, she is interested in how SP-A regulates degranulation, either directly or indirectly, of two important cell types in asthma: mast cells and eosinophils. More recently, Dr. Ledford’s research has focused on understanding how genetic variation within human SP-A2 alters functionality of the protein in relation to eosinophil activities and how this translates to characteristics observed in human asthma.

R. Clark Lantz, PhD Exposure to environmental toxicants alters lung structure and function and leads to chronic lung disease, including cancer. Current investigations are examining the effects of exposure to environmentally relevant doses of arsenic and uranium. Arsenic is a naturally occurring metalloid found in water, soil and air. Exposure to inorganic arsenic occurs worldwide through environmental (contaminated drinking water, air, food and domestic fuel sources) and occupational exposures (smelting industries, pesticide production). In addition to its association with non-malignant diseases, arsenic is of major worldwide health concern because of its carcinogenic potential in humans. Epidemiologic studies have associated arsenic exposure with an increased risk of multiple human cancers including lung, skin, bladder, kidney, liver and stomach cancers. Our current research is focusing on two models to examine the effects of arsenic in the lung. One model relies on exposure to arsenic during lung development, both in utero and postnatally. We have shown that exposure of pregnant female mice and their offspring to 50 or 100 ppb as arsenic in drinking water resulted in altered pulmonary function in 28 day old animals. Airways were more responsive to bronchoconstriction. These changes were specific for exposure during development and were not reversible if arsenic was withdrawn. Associated with these functional changes, arsenic exposure resulted in a dose-dependent increase in airway smooth muscle and alterations in airway connective tissue expression. We are currently analyzing mediators that may be involved in this response to arsenic. In addition, we are beginning investigations into the effect of inhalation of arsenic on lung development. We are also currently using in vitro airway epithelial cell cultures to determine the effects of arsenic on wound repair and epithelial barrier function. In collaboration with Dr. Scott Boitano, we have been able to show that arsenic inhibits wound repair. This may be due in part to arsenic- induced alteration in calcium signaling. We have also been able to show that arsenic alters expression of epithelial junctional proteins and decreases epithelial barrier resistance. Research is also on going to identify protein alterations in lung lining fluid as biomarkers of exposure and effect. This study uses the technology of proteomics to evaluate and identify biomarkers of chronic environmental exposure to arsenic by evaluating large numbers of proteins simultaneously. We are comparing alterations in protein expression in exposed human populations in Arizona and Mexico, human cell lines, and in vivo rodent studies. Patterns of alterations in protein expression, both common and unique to these different test systems, will be identified. Finally, we are evaluating the chemical genotoxicity of uranium. In addition to its radioactive effects, uranium may also have adverse health effects because of its interactions with cellular macromolecules. We have found that uranium causes DNA damage through forming adducts which results in single strand breaks. In addition, uranium also inhibits double strand break DNA repair in airway epithelial cells. Keywords: pulmonary toxicology, arsenic, early life exposures

The long-term goal of research in my lab is to understand the molecular mechanisms of muscle contraction. I am especially interested in how contractile proteins of muscle sarcomeres regulate the force and speed of contraction in the heart. The question is important from both basic science and clinical perspectives because mutations in sarcomere proteins of muscle are a leading cause of hypertrophic cardiomyopathy (HCM), the most common cause of sudden cardiac death in the young and a prevalent cause of heart failure in adults. Myosin binding protein-C (MyBP-C) is a muscle regulatory protein that speeds actomyosin cycling kinetics in response to adrenaline (b-adrenergic stimuli) and is one of the two most commonly affected proteins linked to HCM. Currently, the major research focus in my lab is understanding the mechanisms by which cMyBP-C regulates contractile speed and mechanisms by which mutations in cMyBP-C cause disease. In pursuing these interests I have established a variety of approaches to investigate muscle contraction at molecular, cellular, and whole animal levels. Methods include single molecule atomic force microscopy (AFM), mechanical force measurements in permeabilized muscle cells, in vitro motility assays, biochemical enzyme and binding assays, immunofluorescent imaging, knockout/transgenic animal models and the development of a natural large animal model of HCM.

Carol Gregorio, PhD, performs research in her lab that is focused on identifying the components and molecular mechanisms regulating actin architecture in cardiac and skeletal muscle during normal development and disease. Control of actin filament lengths and dynamics is important for cell motility and architecture and is regulated in part by capping proteins that block elongation and depolymerization at both the fast-growing (barbed) and slow-growing (pointed) ends of the filaments. Striated muscle is an ideal model system to test for the functional properties of various actin regulatory proteins due to the precise organization and polarity of cytoskeletal components within repeating sarcomeric units (for example, the ~1 mm long actin filaments are easily resolved by light microscopy). Using this system, she can combine advanced cell biological and biochemical approaches with direct tests of physiological function in live beating muscle cells.The research objectives of the laboratory can be broadly summarized as follows: 1) understanding the cellular mechanisms involved in the assembly, regulation and maintenance of contractile proteins in cardiac muscle in health and disease; 2) deciphering the mechanisms critical for precisely specifying and maintaining the lengths of actin filaments; 3) discovery of novel models of de novo cardiac muscle assembly, with special emphasis on differentiating murine embryonic stem (ES) cells to study all stages of heart muscle development. Actin is an indispensable structural element of cells and is the major component of heart muscle. Changes in actin, caused by genetic mutations, which have been identified in humans, are a frequent cause of several forms of cardiomyopathy. Her lab is determining how genetic defects in this protein affect muscle force generation and muscle contraction, leading to sudden cardiac death.

Hendrikus Granzier, PhD, studies the mechanisms whereby the giant filamentous protein titin (the largest protein known) influence muscle structure and function. His lab has shown that titin functions as a molecular spring that mediates acute responses to changing pathophysiological states of the heart. They also study the role of titin in cardiac disease, using mouse models with specific modifications in the titin gene, including deciphering the mechanisms that are responsible for gender differences in diastolic dysfunction. An additional focus of Dr. Granzier’s lab is on nebulin, a major muscle protein that causes a severe skeletal muscle disease in humans. Based on previous work, they hypothesize that nebulin is a determinant of calcium sensitivity of contractile force. To test this and other concepts, he uses a nebulin knockout approach in the mouse. Research is multi-faceted and uses cutting-edge techniques at levels ranging across the single molecule, single cell, muscle, and the intact heart. His research group is diverse and has brought together individuals from several continents with expertise ranging from physics and chemistry to cell biology and physiology.

Dr. Thomas Doetschman, PhD, Biochemistry & Biophysics, University of Connecticut, has been involved in cardiovascular research for over a decade through investigations into the cardiovascular roles of the three TGFβ ligands and FGF2 ligand isoforms in genetically engineered mice. These mice have determined that TGFβ2 plays major roles in heart and vascular development and for maintenance of valvular and large vessel integrity in the adult and that both the TGFβ1 and FGF2 are involved in adult heart disease.His work has also demonstrated roles of TGFβ in cancer and immunology. He found that a major function of TGFβ1 is to inhibit autoimmunity and to establish homeostatic balance between immune regulatory and inflammatory cells. He has shown that an imbalance in the latter is critical in the tumor suppressor function of TGFβ in the colon.Dr. Doetschman has also played an important role in the development of the mouse genetic engineering field. He has been responsible for the establishment of 3 mouse genetic engineering facilities, in Cincinnati OH, Singapore and the University of Arizona’s BIO5 Institute. Keywords: "Cancer", "Microbiome", "Mouse Genetic Engineering", "Connective Tissue Disorder"