Project Abstract The thyroid gland is a regulatory organ within the endocrine system vital to many essential processes including breathing and heart rate, metabolism and body weight, menstrual cycles, and body temperature. Hypothyroidism is a common disease especially among the elderly, affecting 5–20% of women and 3–8% of men, and is on the rise in the United States. Thyroid hormone replacement therapy is used for treatment of hypothyroidism but suffers from various problems with therapy optimization and dose adjustment. Our main goal is to determine whether ultrasound can serve as a non-invasive and non-pharmacological method for treatment of hypothyroidism. Here, we propose a novel exploratory study to determine if and how ultrasound may stimulate and control thyroid gland function such as synthesis and release of metabolic hormones triiodothyronine (T3) and thyroxine (T4) in a physiologically relevant context. Our previous and ongoing research work has shown that low intensity therapeutic ultrasound releases insulin from pancreatic beta cells and rodent pancreas at physiological levels without compromising cell viability. This finding opens the doors for possible use of ultrasound therapy in ameliorating secretory defects in other endocrine diseases. The long-term goal of our collaborative research program among Schools of Engineering, Biological Sciences and Medicine at The George Washington University is to develop a mechanistic understanding of the role of therapeutic ultrasound in enhancing release of hormones as a potential treatment of various endocrine diseases. The main objective of this proposal is to determine whether and in what way ultrasound may impact release of thyroid hormones in an in vitro rodent thyroid gland model. Specific Aim 1 of this research work will focus on determining the effectiveness and safety of ultrasound stimulation of the thyroid gland for release of metabolic hormones with the hypothesis that ultrasound treatment promotes release of endocrine thyroid hormones T3 and T3 with little or no other secretory products being released. Specific Aim 2 will focus on determination of mechanisms of ultrasound impact on release of thyroid metabolic hormones with the hypothesis that the mechanism of ultrasound action on the release of thyroid metabolic hormones T3 and T4 is related to the transport of sodium ions and generation of hydrogen peroxide. If shown successful, our proposed approach may open new strategies to combat various endocrine and metabolic diseases.