Progress 09/01/11 to 08/31/12
Outputs
OUTPUTS: After successfully completing the preliminary study, we began our sample analysis based on our endpoints originally proposed as well as those collected from intramural and extramural collaborations. The additional endpoints are related to the effects of inflammation on zinc, retinoids, and arginine levels; these have produced results that have opened further avenues of research. The graduate student (Michael Flock) received training to perform the retinoid analyses. The post-doctoral research fellow (Ann Skulas-Ray) acquired further scientific expertise in these new research areas. The results of the pilot study were presented at the Experimental Biology 2012 conference in San Diego, CA and the Graduate Research Exhibition (2012) on the Penn State Campus. The graduate student (Michael Flock) who presented the results earned a second place award for his work. In addition, we enrolled 125 participants for the main trial. Clinical data and sample collection was completed in September, 2012 and sample analysis is underway. The post-doc presented the results of the study at the meeting of the International Society for the Study of Fatty Acids and Lipids (2012) in Vancouver, Canada. She also presented talks on the roles of omega-3 fatty acids as a nutrient, supplement, and drug at a research symposium in San Diego, California and an invited seminar at Johns Hopkins University. Results from the main trial are expected to be presented at the Experimental Biology conference in 2013. Dissemination: Post-doc presented the following seminars / satellite symposium to discuss omega-3 fatty acids and the induced inflammation model as a research tool: Skulas-Ray, AC. 2011. Inflammation Challenge: Human Endotoxemia as a Nutrition Research Model for Studying Omega-3 Fatty Acids. The Pennsylvania State University, Department of Nutritional Sciences Colloquium. University Park, PA. October 3, 2011. Skulas-Ray, AC. 2012. Omega-3 Fatty Acids and Cardiovascular Disease. American Society for Nutrition Satellite Symposium: The Global Nutrition Transition: The Role of Lipid Supplementation. San Diego, CA. April 20, 2012. Skulas-Ray, AC. 2012. Omega-3 Fatty Acids and Cardiovascular Disease: Bridging Nutrition and Medicine. Johns Hopkins School of Public Health Seminar Series. May 3, 2012. Baltimore, MD. PARTICIPANTS: Dr. Penny Kris-Etherton, PI, maintained her role in providing oversight of all study procedures and communications. Dr. Sandeep Prahbu and his graduate student are in the process of finalizing the protocol necessary for measuring lipid mediators. Mike Flock conducted the clinical study and had the lead role in recruitment, study coordination, and sample/data collection. He has gained extensive clinical trial experience. Ann Skulas-Ray assisted in telephone screening of potential participants. Jennifer Fleming (the Research Study Coordinator) and Ann Skulas-Ray continued in their roles of corresponding with the FDA and IRB, including extensive work to develop a new Investigational New Drug (IND) application including an Investigators Brochure. Ann Skulas-Ray established a Data Safety and Monitoring Board and managed communications with them. All team members participated in study-related problem solving (e.g. unexpected symptom reporting and voluntary hold.) In addition, Mike Flock completed the PhD-required coursework and passed his comprehensive exam. Previous partnership with Nordic Naturals was maintained and they provided all FDA-required materials for completion of the Investigator Brochure required for obtaining a second IND. Previous collaborations with University investigators including Catherine Ross (retinol metabolism) and David Soybel/Shannon Kelleher (zinc metabolism) have been maintained. They are providing the expertise and training necessary to assess effects of inflammation on micronutrient metabolism. Professional development: An undergraduate honors thesis was developed for Elizabeth Weiner to assess the potential influence of sleep quality and physical activity on inflammatory responses to endotoxin challenge. She has received extensive training in scientific research and statistical modeling. A pre-medical undergraduate student (Allison Cherry) assisted in clinical aspects of the study and gained valuable laboratory and clinical experience. A registered nurse, Beth McKee was hired to conduct the clinical procedures and provide participant oversight. TARGET AUDIENCES: The post-doc presented an educational seminar on the use of a new research model (provoked inflammation) to a general nutrition audience and university faculty in an effort to stimulate ideas for advancing nutritional science and gain collaborations. PROJECT MODIFICATIONS: Due to extended difficulties in obtaining the IND approval from FDA we were not able to complete the endotoxemia challenge on all 125 participants, as anticipated. Therefore, our plan is to modify our analytical approach to assay the erythrocyte omega-3 content as one of the predictors of inflammatory responses on the smaller number of participants receiving endotoxin in each treatment group. We are in the process of trying to include a metabolomics component to the study to capitalize on the dose response study design.
Impacts
The results from the preliminary trial provided information that the low dose endotoxemia model was safe and effective in humans for inducing a mild inflammatory response. In addition, we adopted several new methodologies to make cell isolation and sample processing more efficient. The statistical modeling and significant findings from the pilot study will be adopted to help guide the analyses conducted for the main trial. Supplemental fish oil was well tolerated at all doses provided.
Publications
- Flock MR, Skulas-Ray AC, Prabhu KS, Fleming JA, and Kris-Etherton PM. Low-dose endotoxemia as a human model of inflammation. Experimental Biology Annual Meeting. San Diego, CA. April 22, 2012.
- Skulas-Ray AC. 2012. Human endotoxemia as a research model for studying the effects of fatty acids on induced inflammation. 10th Congress of the International Society for the Study of Fatty Acids and Lipids. May 29th, 2012. Vancouver, Canada.
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Progress 09/01/10 to 08/31/11
Outputs
OUTPUTS: A preliminary study was conducted to establish the protocol for low dose LPS administration to a small subset of humans in preparation for our main study. In addition, this study served to establish the effectiveness of a very low dose endotoxmia challenge in producing an inflammatory response. The results of our preliminary study were presented by the project's post-doctoral fellow at the 12th annual Bioactive Lipids in Cancer, Inflammation and Related Diseases conference in Seattle, WA. In addition, the post-doctoral fellow presented the research design and preliminary study findings as an educational seminar for the Department of Nutritional Sciences at Penn State. The seminar aimed to facilitate the understanding and use of a new research model (provoked inflammation). Additional collaborative bridges have been formed with faculty within and beyond the Penn State Department of Nutritional Sciences. The post-doctoral fellow has been training other lab members in cell isolation and statistical techniques that are being developed and used on this project. PARTICIPANTS: Jennifer Fleming (lab manager) completed IRB approvals and obtained FDA approval to receive endotoxin. Developed project forms. Assisted in design of preliminary trial. Initiated clinical trials registries. Coordinated all aspects of approvals communications with FDA and IRB. Ann Skulas-Ray (post-doc) assisted Jennifer Fleming with approvals and form development. Lead scientific design aspects of preliminary trial. Executed preliminary trial (recruitment and study visits). Interpreted and disseminated preliminary trial findings at a conference and departmental symposium. Communicated with master IND holder to obtain to obtain endotoxin supply. Michael Flock (graduate student) received extensive training on conduct of clinical trials with specific emphasis on specialized skills necessary for this project (monitoring for endotoxemia model, specialized specimen processing). Managed clinical trials registries. Assisted in execution of preliminary study. Built collaborative bridge within nutritional sciences to assess retinol metabolism in acute inflammation. Passed candidacy exam and took coursework relevant to establishing scientific growth necessary for independent contributions to the project. Performed independent literature reviews to build expertise in the project area. Penny Kris-Etherton (PI) mentored members of project team and oversaw study progress. Mosuk Chow (biostatistician) provided statistical consulting for modeling repeated measures data. Partner Organizations: A partnership was established with Nordic Naturals. The PI, lab manager, and post-doc worked with Nordic to develop blinded oemga-3 fatty acid capsule kits for the project. Nordic Naturals donated these kits for the study. Collaborators and Contacts: Collaborations have been built to assess interactions of inflammation and micronutrient metabolism. Specifically, the preliminary trial has resulted in collaborative research between the Kris-Etherton lab and the labs of Catherine Ross (retinol metabolism) and David Soybel/Shannon Kelleher (zinc metabolism)to assess effects of inflammation on micronutrient metabolism. Training or professional development: In addition to specific training and professional described above for the project's post-doc and graduate student, two undergraduate students are receiving training under the mentorship of the study team. One student is anticipated to have an honor's thesis from her experience on the study. Other members of the Kris-Etherton lab have received training on specimen processing and statistical modeling that are being used for this project. TARGET AUDIENCES: Nothing significant to report during this reporting period. PROJECT MODIFICATIONS: After significant delay, the IND approval for use of endotoxin was received in March 2011. After completion of the MTA between Penn State and NIH the endotoxin was provided to us in June 2011 and we began and completed our preliminary study shortly thereafter. The results of our preliminary study confirm our expected outcomes that the low dose endotoxemia model is safe and effective in humans for inducing a mild, resolving inflammatory response with minimal clinical symptoms. Therefore, no major modifications to the study protocol are anticipated at this time.
Impacts
The results of our preliminary study demonstrated that the low dose endotoxemia model was safe and effective in humans for inducing a mild, resolving inflammatory response with minimal clinical symptoms. Therefore we are confident in our technique and methodolgy and are enrolling subjects for our main clinical trial.
Publications
- No publications reported this period
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Progress 09/01/09 to 08/31/10
Outputs
OUTPUTS: During the period of this report all relevant personal were trained in Biosafety and working with human subject. In addition, our applications to the Institutional Review Board (IRB) for working with human subjects was prepared, revised, reviewed and approved. Materials that were developed to accompany the application include: Telephone screening forms and recruiting materials, Clinical screening and data collection forms, Endpoint collection and Blood allocation sheets. FDA application for use of LPS endotoxin was submitted. PARTICIPANTS: Dr. Penny Kris-Etherton (P.I.) and Jennifer Fleming (Coordinator) worked together to receive IRB approval and submit IND application to FDA. TARGET AUDIENCES: Nothing significant to report during this reporting period. PROJECT MODIFICATIONS: Delay in proposed timeline; FDA approval for use of endotoxin not yet received.
Impacts
Methods and techniques for blood sample collection and analysis were developed and mastered.
Publications
- No publications reported this period
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