 |
(From left to right) Todd Wyatt, Ph.D., Lisa Chudomelka, administrative research associate, Joe Sisson, M.D., Kristina Bailey, M.D., Debra Romberger, M.D., and Diane Allen-Gipson, Ph.D., are all part of the pulmonary, critical care, sleep & allergy section in the department of internal medicine, which has recently secured an impressive amout of research funding. |
As everyone knows, grants don’t just appear at the lab door without a great deal of effort and persistence in developing hypotheses and data, publishing manuscripts, crafting a grant proposal and, finally, convincing a study section that your work is worthy of funding. While the occasional proposal gets funded outright, in the current funding climate, it can takes years to fund one’s research.
Take the pulmonary, critical care, sleep & allergy section in the department of internal medicine as an example of persistence. Not only did the section succeed in receiving five extramural grant awards totaling more than $3.8 million in direct costs, 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 last bit of good news came when Dr. Diane Allen-Gipson received notice that her K01 career development award application had been funded.
“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 Dr. Lynell Klassen, Henry J. Lehnhoff Professor and chairman of the department of internal medicine.
“This will be the model that is used by most successful and expanding research programs.”
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 (cigarette smoke +/- alcohol and organic dust, respectively) on kinase activation, and both Dr. Sisson and Dr. Wyatt are focused on the cilia.
Dr. Allen-Gipson is examining how the lung heals itself after injury.
“Our efforts were greatly facilitated by the careful work that Lisa Chudomelka put into these grants,” Dr. Sisson said. “Her skill as a specialist in grant and publication management allowed our investigators to focus on the science and not on the complicated logistics of the submission and regulatory processes. We could not have met our deadlines for these proposals and resubmissions without her help and patience.”
The following is a brief description of the four grants:
Ethanol-mediated Cilia Motility Dysfunction
- Principal investigator: Joe Sisson, M.D.
- Co-investigator: Todd A Wyatt, Ph.D.
- Funding source: R01, National Institute on Alcohol Abuse and Alcoholism
- Amount: $1.64 million in direct costs 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 J Romberger, M.D.
- Co-investigator: Todd A Wyatt, PhD, 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 in direct costs 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
Our interest is the overall study of 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. This ciliary beating has been shown to be regulable in that increases in cilia beating can be induced by cell exposure to various pharmacologic agents, particles, mechanical stress, and changes in temperature and pH. 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 A. Wyatt, Ph.D.
- Funding source: K01, 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 us to hypothesize that: Adenosine modulates airway homeostasis and wound repair.
To test this hypothesis we propose the following four Specific Aims:
- 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 L. Bailey, M.D.
- Primary sponsor: Joe Sisson, M.D.
- Co-mentor: Debra J 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 innate 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 upregulates airway epithelial cell TLR2. This research plan will help answer several questions including: defining the time course and concentration-dependence of TLR2 mRNA and protein expression triggered by alcohol in airway epithelial cells; identify the roles of nitric oxide production, ROS (reactive oxygen species) production and NFB activation in alcohol-triggered TLR2 upregulation in vitro; and determine the impact of alcohol-triggered TLR2 upregulation on lung inflammation in an in vivo model of alcohol-fed mice exposed to intratracheal Streptococcus pneumoniae.