Dr. Mary T. Weis 972.881.5725 mweis@ccccd.edu Study Grant Proposal Rationale: The immune system is one of three major homeostatic controls for body balance. The key to coordinate activities between the nervous, endocrine, and immune systems is cellular communication. The immune system uses a group of chemical mediators to communicate to and between various body cells. There are many types of cytokines and they are grouped based on their source type or processes controlled. For a healthy balance, negative feedback is usually necessary to make proper adjustments. During injury to any body cell will result in a non specific inflammatory response which releases additional chemicals that work in a positive feedback cycle which continues until it is somehow turned off. Controlling the amount and type of chemicals is important to prevent continued destruction of cells without a continued injury stimulus. Inability to control immune chemical signals can lead to serious imbalances in homeostasis and potentially create debilitating diseases. Discussion: Depending on the site of injury and the nature of the invader, the immune reaction will differ. Nonspecific and specific immune cells will migrate to the injured area, become activated, and begin their task of destroying the pathogen. Chemical messengers produced by white blood cells are known as cell derived mediators and include various types of prostaglandins, leukotrienes, cytokines, PAF, histamine, and kinins. The second type of chemical signals relate to plasma derived mediators which include complement and interferon. While some of the acute functions of these chemicals have been studied, the underlying initial result of these chemicals during inflammatory response creates a clinical picture of a painful, red, swollen, and warm area. Since this response should only last as long as the disease causing organism exists, once this occurs, the injured area should return to normal function. The actual process by which this happens is only now being understood. The key element seems to be a phenomenon called apoptosis or programmed cell death. There are two theories about this process: that the cells receive some type of “death signal” or else they do not receive the “stay-alive signal.” If the inflammatory response continues over a longer period of time than is necessary, then chronic inflammation may develop and can potentially create further problems. In the last 2-3 years, more immune chemicals have been discovered and their actions for body defenses are still being researched. Drug companies respond to this research by creating treatments that enhance or block reactions to change the response and the effects of the immune reaction. Some well-known examples of these drugs include corticosteroids and aspirin. In addition, recent discussion and research about inflammatory mediators has directed a rethinking of proper nutrition for dietary requirements. This new research is now being published showing the link of chronic inflammation to diabetes, Alzheimer’s, and even heart disease. Long term effects of these cytokines on the body’s metabolic functions as it relates other types of chronic diseases and certain cancers is only now being discussed. As a scientist and teacher, I am interested in focusing on these immune chemicals and their short and long term actions in the body. Western medicine is excellent at treating acute injury cases, but we fall short in dealing with most of the chronic and debilitating diseases for our human and animal patients. The immune system is extremely complex and the more we discover, the more we realize the intricate balance of communication for proper function. Proposed Topic: “Inflammation: Immune Protection or Harmful Process?” Questions to be explored: a) b) c) d) What are the currently known acute functions of inflammatory mediators? What are the possible chronic effects of these inflammatory mediators? Which diseases or conditions have an initial inflammatory component? What are the latest diagnostic tests to determine beneficial or harmful chemical mediators of the immune system? e) What are the current therapies (drugs, nutrition, and alternative) related to controlling cytokines and promoting long term health? Since this information will involve the most recent, cutting edge research, I will start in the mid spring through early summer by reviewing current and recently published literature. During summer II, my study grant will involve reading and compiling updates on immunology, inflammation, and related cytokines using selected textbooks, medical journals, and related medical websites based on the plan below. The list of current texts and journals in the work plan are examples of the types of information I will be collecting prior to analyzing the latest information. I fully expect that my literature review will continue to expand to include additional lists of texts and medical journal articles that have the most current information available for my proposed study grant. Summer II Weekly Work Plan Week 1: Immunology review of current concepts and the process of inflammation in the immune defense. Immunology: An Introduction, Ian Tizard, 2003 The natural history of the systemic inflammatory response syndrome, MS RangelFrausto, JAMA 1995 Jan 11; 272(2): 117-123 Systemic Inflammatory Response Syndrome, Steven Burdette, E-medicine 2006 Immunological response to infection and its role in septic shock, CL Casey, Critical Care Clinician 2000; 16:193-211 Week 2: Acute and chronic effects of inflammatory mediators Foye’s Principles of Medicinal Chemistry, David A Williams, PhD, 2002 Pro-inflammatory-anti-inflammatory cytokine dynamics mediated by cytokinereceptor dynamics in monocytes, Seymour, R, Mathematical Medicine and Biology 2001; 18:159-192 Differential inhibition of inflammatory cytokine release from cultured alveolar macrophages from smokers and non-smokers, T. Dandrea, Human Experimental Toxicology, 1997 Oct;16(10):577-588 Eicosanoids and inflammatory response, National Academy of Sciences, 2006 p53 as a suppressor of inflammatory response in mice, Elena Komarova, The FASEB Journal 2005; 19:1030-1032 Acute –phase proteins and other systemic inflammatory responses to inflammation, C. Gabay, NEJM 1999; 340:448-454 Cutting Edge: an endogenous pathway to systemic inflammatory response syndrome-like reactions through Toll-like receptor, GB Johnson, J Immunology 2004; 172:20-24 Week 3: Chronic diseases with known or proposed inflammatory component and diagnostic tests for immune chemicals related to inflammation Inflammatory cytokine levels correlate with amyloid load in transgenic mouse models of Alzheimer’s disease, Nikunj Patel, Journal of Neuroinflammation 2005; 2:9 Inflammatory Cytokines as Risk Factors for a First Venous Thrombosis: A prospective Population-Based Study, Sverre Crhistiansen, PLoS medical journal Measurement of inflammatory cytokines by multicytokine assay in tears, L. Malvitte, British Journal of Ophthalmology, 2006; 91:29-32 Aging and Inflammation, Life Extension Foundation, 2004 Heart Disease and the inflammatory response, Wolfgang Koenig, BMJ 2000 July 22; 321(7255): 187-188 TNF-{alpha} neutralization in cytokine-driven disease: a mathematical model to account for therapeutic success in rheumatoid arthritis but therapeutic failure in systemic inflammatory response syndrome, M. Jit, Rheumatology, 2005; 44: 323331 The inflammatory response: friend or enemy for muscle injury? H. Toumi, British Journal of Sports Medicine 2003; 37:284-286 Systemic Inflammatory Response in Progression to Severe Sepsis in Critically Ill Patients, Corianne Alberti, American Journal of Respiratory and Critical Care Medicine 2005; Vol 171:461-468 New-onset hypertension and inflammatory response/poor outcome in acute ischemic stroke, M.Rodriguez-Yanez, Neurology 2006; 67:1973-1978 The cellular inflammatory response in human spinal cords after injury, Jennifer Fleming, Brain 2006; 129(12):3249-3269 Inflammatory Mediators in Gastrointestinal Defense and Injury, JL Wallace, Experimental Biology and Medicine, 2001; 226(11): 1003-1015 Week 4: Nutritional therapies to control inflammation and drug therapies that affect inflammation The Inflammation Syndrome: The complete Nutritional Program to Prevent and Reverse Heart Disease, Arthritis, Diabetes, Allergies, and Asthma, Jack Challem, M.D., 2003 Differential Induction of Pro- and Anti- Inflammatory Cytokines in Whole Blood by Bacteria: Effects of Antibiotic Treatment, JT Frieling, Antimicrobial Agents and Chemotherapy, 1997; July: 1439-1443 Reduced prevalence of AD in users of NSAIDS and H2 receptor antagonists: The Cache County Study, Anthony Breitner, Neurology 2000; 54:2066-71 Week 5: Alternative therapies that affect inflammatory chemicals and lifestyle changes for immune health Stop Inflammation Now! : A step-by-step Plan to Prevent, Treat, and Reverse Inflammation, Richard M. Fleming, M.D., 2004 Systemic Inflammation and Surgery, Susan Conova, In Vivo 2002, Vol 1: Issue 2 Herbal Medicine: Expanded Commission E Monographs, Bluemthal, 2000 Positive Energy, Judith Orloff M.D., 2005 Conclusion: Because the immune system is so important to long term health and because immune chemicals can have all types of effects, I would like to research and review the immune cytokines related to their short and long term affects during the inflammation process. The immune system as an undergraduate biological subtopic is covered at various levels of detail depending on the course. Being able to focus my studies on these important chemicals and their functions will allow me to not only help students and clients understand long term inflammatory effects, but to help them make decisions on proper therapies for themselves as well as their patients and pets. As a teacher and scientist, I will be able to have an in-depth understanding and preparedness to answer questions and determine proper treatments for my patients at all stages of their lives. Presentations to interested faculty, nursing students, and community health members either face to face or via the web can be conducted.