Grants are the measuring stick for every scientist in academic research. The pulmonary, critical care, sleep & allergy section in the department of internal medicine at the University of Nebraska Medical Center recently added five grants totaling $3.8 million to its yardstick.
Not only did the section succeed in receiving five grants, but all five notices came between Aug. 1 and Sept. 30.
“It has been a concerted effort by a number of investigators to get these grants funded,” said Joe Sisson, M.D., Larson Professor and chief of the pulmonary, critical care, sleep and allergy section. Dr. Sisson said the string of grants is just one example of how strong the section has become.
“These grants build upon the long track record of the research in this department by the many outstanding faculty members who have and continue to receive funding,” he said. “We also want to acknowledge the heroic efforts our laboratory staff and post-doctoral fellows put into these proposals related to preliminary data and pilot experiments. This is truly a team effort."
The notices began arriving in early August when Debra Romberger, M.D. received funding for her study on the effect of organic dust on the lungs. Next, Dr. Sisson learned that his 15-year-long grant from the National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism to investigate mucociliary function would be funded for another five years. Todd Wyatt, Ph.D., then received funding for his VA Merit Review proposal to study epithelilal cell signaling on cilia, and Kristina Bailey, M.D., landed a laboratory research fellowship from the National Research Service Award. The final grant came when Diane Allen-Gipson, Ph.D., landed a career development award.
“The pulmonary section’s academic success has been based on developing highly interactive and collaborative research programs that build on the combined investigative strength of individual faculty members,” said Lynell Klassen, M.D., Henry J. Lehnhoff Professor and Chair of the Department of Internal Medicine.
The success of each project is independent of the others, but they are all related, demonstrating a collaborative research environment that is fostering greater success than if each investigator worked alone. For instance, Drs. Sisson, Wyatt and Bailey are all examining the effect of alcohol on the lung, particularly different signaling mechanisms that alcohol may either trigger or blunt. Likewise, Drs. Wyatt and Romberger are both considering the impact of environmental exposures such as cigarette smoke, alcohol and organic dust, and both Drs. Sisson and Wyatt are focused on the cilia. Dr. Allen-Gipson is examining how the lung heals itself after injury.
The following is a brief description of the five grants:
Ethanol-mediated Cilia Motility Dysfunction
Principal investigator: Joe Sisson, M.D.
Co-investigator: Todd Wyatt, Ph.D.
Funding source: National Institute on Alcohol Abuse and Alcoholism
Amount: $1.64 million over 5 years
Heavy alcohol intake is known to damage the ability of the lung to protect itself from infections such as pneumonia and bronchitis because of the damage it does to the mucociliary apparatus, the lung’s first line of defense against infection. The mucociliary apparatus produces mucus which traps inhaled particles and propels them out of the lung via the cilia – the fingerlike projections of the lung lining. Alcohol profoundly injures the delicate mucociliary apparatus by altering critical proteins called kinases, molecules that regulate cell functions in the lung cilia. While it has been established that alcohol causes this problem, it is not known how long it persists if alcohol is removed and exactly how alcohol alters these important kinase-dependent functions in cilia. This study will address two questions: Is alcohol-driven impairment of mucociliary function preventable or reversible and which cilia proteins are affected by alcohol?
Organic Dust Epithelial PKC Activation & Airway Disease
Principal investigator: Debra Romberger, M.D.
Co-investigator: Todd Wyatt, Ph.D., Myron Toews, Ph.D., William West, M.D., and Jane Meza, Ph.D.
Funding source: R01, National Institute for Occupational Safety and Health
Amount: $920,000 over 4 years
Exposure to organic dusts is a cause of airway disease, including chronic obstructive pulmonary disease (COPD), as many as 20 percent of all COPD cases are attributed to occupational exposures. In rural areas, an important source of dust exposure occurs in hog confinement barns. Persons exposed to hog barns have airway inflammation and an increased incidence of COPD. Although many substances are present in hog barn dust that induces inflammation including endotoxins, actual mechanisms leading to COPD are not well defined. Understanding mechanisms of hog barn dust-induced airway disease is relevant in developing both targeted treatment and prevention strategies.
The objective of this proposal is to define mechanisms by which hog barn dust activates epithelial cell protein kinase C (PKC) and the role of PKC in airway inflammation associated with chronic bronchitis occurring in confinement facility workers and to determine the role of hog barn dust-related lysophosphatidic acid, an important lipid mediator, in modulating dust effects on PKC and inflammatory responses.
Protein Kinase C Regulation of Airway Epithelial Cell Ciliary Decreases
Principal Investigator: Todd Wyatt, Ph.D.
Funding source: Veterans Affairs Merit Review
Amount: $686,000 over 4 years
This study will investigate chronic inflammatory lung disease mechanisms within the context of combined alcohol use and cigarette smoking. The airways of smokers who drink alcohol are subject to an increased susceptibility of viral and bacterial infection, suggesting a compromise in the protective mucociliary apparatus. A great deal of research focuses on the innate and adaptive immune mechanisms in response to inhaled toxins and pathogens. However, the first line of defense against such inhaled particles is the mucociliary apparatus, which produces mucus that traps inhaled particles and propels them out of the lung via the cilia. Mucociliary clearance is orchestrated via the beating action of the ciliated cells lining the airways. Increases in cilia beating can be induced by cell exposure to various pharmacologic agents, particles, mechanical stress, and changes in temperature. While the stimulatory mechanisms of ciliary beating have been widely studied, little has been investigated concerning agents and mechanisms of cilia slowing. It is believed that ciliary beating is slowed by exposure to a combination of cigarette smoke and alcohol. The potential impact of this work on veterans’ health care is significant considering the enormous problems that cigarette smoking and alcohol abuse play in the veteran’s population. Likewise, chronic lung diseases are three times more likely to afflict veterans than the population at large, making this proposed research extremely relevant to the needs of veterans.
Adenosine Regulation of Airway Wound Repair
Principal investigator: Diane Allen-Gipson, Ph.D.
Co-investigator: Todd Wyatt, Ph.D.
Funding source: National Heart, Lung, and Blood Institute
Amount: $680,000 in direct costs
Adenosine produces a wide variety of physiological effects through activation of four cell-surface receptors, A1, A2A, A2B and A3. Through these receptors, adenosine can either protect or damage tissues depending on the receptor(s) activated. As a potent regulator of inflammation, adenosine initiates the first stage of wound-healing. If repair responses restore normal tissue architecture, function will be preserved. Our preliminary data demonstrate the multidimensional properties of adenosine in the airway, particularly in understanding receptor regulation and signaling. These findings led to the hypothesis that: Adenosine modulates airway homeostasis and wound repair. To test this hypothesis, four specific aims will be studied: 1. Identify the adenosine receptor(s) present on normal and wounded airway epithelium; 2. Characterize and determine the effects of adenosine on airway wound healing and modulation of wound repair processes; 3. Identify the signaling pathways that control adenosine-mediated homeostatic and wound repair processes in airway epithelium; and 4. Characterize the effects in vitro of adenosine-mediated epithelial homeostatic and wound repair processes using primary mouse epithelial cells. These proposed studies could lead to novel therapies for inflammatory airway diseases, such as COPD.
Alcohol Modulates TLR2 Signaling in Airway Epithelium
Principal investigator: Kristina Bailey, M.D.
Primary sponsor: Joe Sisson, M.D.
Co-mentor: Debra Romberger, M.D.
Funding source: NRSA, National Institute on Alcohol Abuse and Alcoholism
Amount: $110,000 including institutional allowance
Alcohol abuse is well known to have harmful effects on the lung. For example, heavy alcohol intake increases the risk for developing pneumonia, acute respiratory distress syndrome (ARDS), and bronchitis. In these alcohol-associated lung diseases, alcohol intake is thought to “prime” the lung for subsequent injury, such as viral infection, trauma or sepsis. The first line of defense in the immune system of the lung is the airway epithelium, which expresses toll-like receptors (TLR). When TLR2 is activated, it initiates the cellular inflammatory response to gram-positive microbial invasion. Interestingly, it has recently been observed that alcohol strongly regulates airway epithelial cell TLR2. This research plan will help answer several questions such as defining the time course and concentration-dependence of receptors and the protein expression triggered by alcohol in airway epithelial cells.
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