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Oxytocin: Improving measurement sensitivity and specificity


OBJECTIVE: Improve oxytocin measurement techniques by developing quantitative assays to measure oxytocin more sensitively and specifically, particularly to discriminate between the 9- and 12- amino acid versions. Measurements of these two forms will be conducted in an in vivo system to determine their variance under experimental conditions known to affect oxytocin levels. DESCRIPTION: Oxytocin is a hormone widely known for its role in reproduction and childbirth. More recently its role as a neuromodulator has been highlighted, particularly in facilitating pair bonding, maternal interactions, and trust behaviors (1,2). An explosion of research on the effects of oxytocin has ensued, and the hormone is listed in 213 ongoing or completed clinical trials on Oxytocin also affects behaviors relevant to national security. Oxytocin can impact behaviors ranging from whether two individuals trust each other, how someone reacts to stress, and even wound healing. Therefore, developing oxytocin assays with improved sensitivity and specificity will provide the necessary tools to understand the function of this important neurohormone (3,4). These tools can be used across DoD research programs in areas such as stress resilience, human decision making, and PTSD treatment to enable advances in technology development relevant to the warfighter. Unfortunately, from an experimental perspective, oxytocin is present at low levels in the body. Basal blood levels of oxytocin are in the pg/mL range (2). This low biological level makes accurate measurements of oxytocin difficult. In the laboratory, oxytocin is often measured by immune-assays, which involve the binding of anti-bodies to the molecule of interest (5). These molecular methods have improved somewhat to include extraction steps that concentrate the oxytocin samples. However, sensitivity is still an issue. While detection is usually possible in the blood, measuring oxytocin from other more readily available samples (i.e. saliva or sweat) is often not possible because the levels are undetectable. Innovative assay methods that significantly improve oxytocin assay sensitivity, particularly enabling measurement in these less traditional samples would be a breakthrough to this research field. Recent studies have shown the regulation of oxytocin to be a complex process. In particular two forms of oxytocin have been identified. A 10-12-amino acid pro-hormone is first produced, and then, at some point, may be cleaved to a 9-amino acid hormone. This shortened form is the active neuropeptide, oxytocin, known to bind to the oxytocin receptor and credited with oxytocin"s behavior altering effects. The biological role, if any of the 12-amino acid pro-hormone is unknown, but has been associated with atypical social behaviors in autism and possibly related to obesity in Prader-Willi syndrome (6,7). Additional forms of different lengths or biologically active metabolites of oxytocin may exist, as well. Current assay techniques are non-specific to these different forms of oxytocin, failing to differentiate bioactive from potentially inert forms. This lack of specificity may add significant noise to a measurement of very low hormone levels (5). New detection techniques that distinguish between these different forms of oxytocin may elucidate a functional role for this complex biological regulation. This technique could help explain seemingly paradoxical findings in the oxytocin literature, regarding its role both in pro-social and pro-stress behaviors. Regardless, more sensitive and specific assay techniques for oxytocin would provide a more accurate picture of the complex regulation of this intriguing neurohormone. Clinical researchers and practitioners would also benefit from such a tool, to aid in understanding oxytocin"s role in social disorders, such as autism, and potential therapeutic application, as demonstrated by its high use in clinical trials. Particularly, the ability to measure different forms of oxytocin, presently impossible, could demonstrate a highly specific biomarker of social and/or stress disorders, or at least altered responses to social and stressful stimuli. PHASE I: Determine the technical feasibility of the proposed measurement technique for oxytocin. Performers will identify an innovative technical approach for the sensitive detection of oxytocin and its derivatives. If possible, performers will conduct proof-of-principle studies to demonstrate that different forms of oxytocin can be reliably detected, using synthetic oxytocin. Phase I deliverables will include a technical report on the proposed technique and an experimental outline for studies necessary to improve assay sensitivity and determine oxytocin species"levels in an in vivo system. PHASE II: Develop and refine the technique identified in Phase I, particularly to increase its sensitivity. In addition, the technique should be used to measure biological oxytocin collected from in vivo animal or human experiments to determine how levels of the long and short forms of oxytocin vary under conditions of stress and social interaction, which have previously shown oxytocin sensitivity. Sensitivity of the new system should be benchmarked against existing detection methods and measurements from in vivo systems compared to detection of known levels of synthetic oxytocin. Required phase II deliverables will include a technical a report detailing the new measurement technique and its results from the above-mentioned comparisons. Findings related to differences in short and long forms of oxytocin under varying experimental conditions (e.g. stress or social interaction) should also be included. PHASE III: Military research laboratories would be very interested in using a highly sensitive and specific oxytocin assay. For example, the Air Force Research Laboratories have been measuring oxytocin with traditional enzyme immunoassay methods for defense applications. An improved assay technique could be used to reanalyze their samples and may shed new light on the problem of developing trust. Other military partners may be interested in this technology or a future derivative for the measurement of oxytocin to understand influence. The DARPA program Narrative Networks is examining oxytocin in this context and would benefit from increased measurement specificity and sensitivity. Developments made under this SBIR effort could be transitioned, in synergy with findings from Narrative Networks, to provide better assays of oxytocin as it changes with narrative influence. The clinical dimensions of oxytocin measurement may also present transition opportunities to the military, since oxytocin has been linked with stress reactions. New measurement techniques will allow clinical scientists to investigate if it plays a role or is correlated with Post-Traumatic Stress Disorder (8). A highly sensitive and specific assay to measure oxytocin in biological samples, including blood, saliva, and sweat would have a number of commercial applications. Biotechnology companies would be interested in refining an improved technique and would likely see additional investment in development and production as a small risk, given the research and commercial need for such an assay. REFERENCES: 1. Carter, CS, Grippo, AJ, Pournajafi-Nazarloo, H, Ruscio, MG, Porges, SW. (2008). Oxytocin, vasopressin and sociality. Progress in Brain Research 170: 331-336. 2. Meyer-Lindenberg, A, Domes, G, Kirsch, P, Heinrichs, M. (2011). Oxytocin and vasopressin the human brain: social neuropeptides for translational medicine. Nature Reviews in Neuroscience 12, 524-538. 3. Gouin JP, Carter CS, Pournajafi-Nazarloo H, Glaser R, Malarkey WB, Loving TJ, Stowell J, Kiecolt-Glaser JK. (2010). Marital behavior, oxytocin, vasopressin and wound healing. Psychoneuroendocrinology 35:1082-1090. 4. Karelina, K, DeVries, AC. (2011). Modeling social influences on human health. Psychosomatic Medicine 73, 67-74. 5. Szeto A, McCabe PM, Nation DA, Tabak BA, Rossetti MA, McCullough ME, Schneiderman N, Mendez AJ. (2011). Evaluation of enzyme immunoassay and radioimmunoassay methods for the measurement of plasma oxytocin. Psychosomatic Medicine. 73:393-400. 6. Green L, Fein D, Modahl C, Feinstein C, Waterhouse L, Morris M. (2001). Oxytocin and autistic disorder: alterations in peptide forms. Biological Psychiatry 50:609-613. 7. Dombret C, Nguyen T, Schakman O, Michaud JL, Hardin-Pouzet H, Bertrand MJ, De Backer O. (2012) Loss of Maged1 results in obesity, deficits of social interactions, impaired sexual behavior and severe alteration of mature oxytocin production in the hypothalamus. Human Molecular Genetics. 21:4703-4717. 8. Olff, M. (2012) Bonding after trauma: on the role of social support and the oxytocin system in traumatic stress. European Journal of Psychotraumatology. E pub April 27, 2012.
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