2005 Annual Report
1.What major problem or issue is being resolved and how are you resolving it (summarize project aims and objectives)? How serious is the problem? What does it matter?
The amount and type of dietary fatty acids play an important role in health maintenance and disease prevention. Different fatty acids and their metabolites regulate signal transduction, gene expression, cell growth, differentiation, and death. Excessive intake of omega-6 fatty acids found in most seed oils has the potential to increase inflammatory diseases, while omega-3 fatty acids found in marine and some seed oils (flax, perilla, and walnuts) have strong
anti-inflammatory effects. The ratio between the dietary omega-6 and omega-3 fatty acids influences the development and progression of several human chronic diseases including cardiovascular disease (CVD), diabetes, arthritis, lupus, inflammatory bowel disease, and many others. CVD alone is responsible for more than one-half of all the deaths in USA and many European countries. Overall goal of our studies is to determine the effects of dietary fatty acids on immune and inflammatory responses and on risk factors for chronic diseases. Specific objectives are:
1. Determine effects of DHA supplementation on risk factors for CVD in hypertriglyceridemic men. 2. Determine effects of omega-6 and omega-3 fatty acids on proliferation and differentiation of granulocytic precursor cells, and elucidate the mechanisms involved. 3. Determine whether different dietary fatty acids modulate the activation of Toll-like receptors, downstream signaling pathways, target gene expression and consequent cellular responses. Specific aim
1 will involve DHA supplementation of hypertriglyceridemic men, and monitoring effects on conventional and novel markers for CVD, markers for diabetes, and gene expression. Specific aims 2 & 3 will involve feeding diets with different fatty acid compositions to animal models, and adding fatty acids to cultured cells. Results obtained will provide the information needed to determine dietary requirements for long chain PUFA, and specific dietary fatty acid based therapies for the prevention and management of inflammatory conditions. This is expected to improve quality of life and may open new avenues for agricultural products. Understanding the mechanisms by which different dietary fatty acids improve health or cause diseases may also identify the metabolic sites that may be regulated by drug therapies.
2.List the milestones (indicators of progress) from your Project Plan.
Specific Aim 1:
Year 1: Subject recruitment, fatty acid supplementation, and sample collection.
Year 2: Continue with that listed for year 1 and start sample and data analysis.
Year 3-5: Sample and data analysis, and preparation of manuscripts.
Specific Aim 2:
Year 3: Conduct experiments with promyelocytic cell lines.
Year 4: Analyze data from experiments with cell lines and prepare manuscripts, conduct experiments with mice.
Year 5: Analyze samples and data from the mice studies, and prepare manuscripts.
Specific Aim 3:
Year 1-3: Determine relative potency of n-3 PUFAs as compared with n-6 PUFAs in inhibiting the activation of Toll-like receptors (TLR) and wheather different TLRs are differently modulated by fatty acids.
Year 1-5: Determine whether TLR4 induced activation of downstream signaling pathways and target gene expressions are also altered by fatty acids.
These are tentative time schedules. We may end up spending more time on some studies and less time on other studies.
4a.What was the single most significant accomplishment this past year?
The results from our previous studies suggested that saturated fatty acids and polyunsaturated fatty acids oppositely modulate Toll-like receptor signaling pathways. Thus, as a functional consequence of such modulation whether subsequent immune function is also affected, was determined. Studies were conducted using dendritic cells isolated from mice and treated with different fatty acids. Co-stimulatory molecule expression and T-lymphocyte activation were determined.
The results showed that saturated and n-3 polyunsaturated fatty acids (PUFAs) reciprocally modulated the dendritic cell functions as a result of corresponding effects of these fatty acids on the activity of Toll-like receptors.
The implication of this finding is that if such results are shown in human studies, saturated fatty acids may enhance but n-3 PUFAs may suppress the risk of development of inflammatory chronic diseases.
4b.List other significant accomplishments, if any.
4c.List any significant activities that support special target populations.
We have obtained funds ($164,861) from the Beverage Institute of Wellness and Health to study the effects of citrus limonoids on serum lipids and markers of inflammation. This study is delayed because of the unexpected delay in procuring the citrus limonoids; we hope that this material will become available within the next 3 months and then we can start this study.
Our USDA-NRI grant (2001-35200-10721) was completed and terminated in December, 2004.
The main goal of the grant was to investigate the mechanism by which dietary n-3 fatty acids suppress tumor cell growth. The major finding of the results from the studies was that dietary n-3 fatty acids suppress PPAR delta which is implicated in promoting cell proliferation, and thereby inhibit cell proliferation.
5.Describe the major accomplishments over the life of the project, including their predicted or actual impact.
This is a new CRIS and this report is for its second year; hence there are no major accomplishments to report other than accomplishments listed under response #4. Our previous CRIS also dealt with the health effects of dietary fatty acids and the accomplishments listed are for the expired CRIS. Research conducted under the expired CRIS showed that increasing total fat intake inhibited several aspects of human immune status. If total fat intake was held constant, increasing the intake of omega-3 fatty acids reduced a number of markers for inflammation (numbers of circulating granulocytes, inflammatory cytokines and eicosanoids), while omega-6 fatty acids had the opposite effects. Omega-3 fatty acids are now used in the management of several inflammatory diseases including, CVD, arthritis, asthma, and adult respiratory distress syndrome (ARDS). We have also shown that the ratio between saturated and unsaturated fatty acids was more critical than the amount of dietary fat in determining serum cholesterol levels. Our studies conducted with CLA supplementation showed no benefit, but several potential risks to humans. Results from our studies have been used by health organizations for making recommendations regarding fatty acid intake.
6.What science and/or technologies have been transferred and to whom? When is the science and/or technology likely to become available to the end-user (industry, farmer, other scientists)? What are the constraints, if known, to the adoption and durability of the technology products?
7.List your most important publications in the popular press and presentations to organizations and articles written about your work. (NOTE: List your peer reviewed publications below).
Manners GD, Breska AP, Kelley DS, and Zunino SJ (2005). Citrus Compound, Ready to Help Your Body. ARS Magazine, Feb 2005, p16-17.
Weatherill, A., Lee, J., Zhao, L., Lemay, D., Youn, H.S., Hwang, D.H. Saturated and polyunsaturated fatty acids reciprocally modulate dendritic cell functions mediated through tlr4. Journal of Immunology. 174:5390-5397, 2005.