Control of homeostasis by trace amine-associated receptors

我的长期目标是确定被称为微量胺的内源性化学物质和检测它们存在的蛋白质（微量胺相关受体；TAAR）的生理作用。TAAR存在于所有脊椎动物的全身，但除了大脑中的TAAR1外，人们对它们的正常作用知之甚少。脑外TAAR最突出的两个部位是鼻腔和胰腺。与许多其他受体不同，TAAR不存在于细胞表面，而是存在于细胞内。这需要微量胺穿过细胞膜，以便与TAAR结合并参与细胞间通讯。我们之前的工作表明，这一过程是由尚未确定的转运体控制的。******就它们在嗅觉中的作用而言，TAAR可以探测到各种生态来源的气味，包括捕食者、变质的食物，甚至可能是信息素。这种检测导致了依赖于性别和物种的先天行为（不需要学习），但这些影响的细胞基础尚不清楚。我们之前的研究表明，微量胺很容易穿过细胞膜，这表明吸入后，微量胺穿过肺膜也可能产生影响。由于吸入微量胺进入血液的影响以前没有被考虑过。我们的初步研究表明，吸入一些（但不是全部）微量胺会改变血糖水平。我们还证实，在胰腺TAAR控制胰岛素释放。然而，TAAR如何做到这一点尚不清楚。******为了实现我们的长期目标，并解决上述知识空白，本提案中的研究将：***1)确定控制痕量胺进入TAAR的转运体，***2)确定TAAR在不同生态来源的环境应激源的适应性反应中的作用，***3)确定TAAR调节胰岛素释放的分子机制。******通过填补这些知识空白，将发现新的调节微量胺功能的分子靶点，这对于阐明微量胺生理在维持机体功能中的作用至关重要。这些目标的识别对于那些研究创伤后应激障碍、糖尿病和肥胖等人类疾病的人未来的转化研究也至关重要。此外，通过确定性别和物种对与生态危害相关的化学物质的特定反应的分子基础，我们将增加对脊椎动物适应性应激反应的理解，以及它们对栖息地变化和生态挑战的生理适应的分子基础。

My long-term goal is to determine the physiological roles of endogenous chemicals called trace amines and the proteins (trace amine-associated receptors; TAAR) that detect their presence. TAAR are present throughout the body in all vertebrate species, but with the exception of TAAR1 in the brain, little is known about their normal roles. Two of the most prominent sites of TAAR outside of the brain are the nasal passages and the pancreas. Unlike many other receptors, TAAR are not present at cell surfaces, rather residing inside the cell. This requires that trace amines cross cell membranes in order to bind to TAAR and participate in cell-cell communication. Our previous work has shown that this process is controlled by transporters that have not yet been identified. ******With respect to their role in the sense of smell, TAAR detect odours from diverse ecological sources including predators, spoiled food, and even putative pheromones. This detection causes innate behaviours (no learning is necessary) that are gender and species dependent, but the cellular basis of these effects are unknown. Our previous work showing trace amines readily cross cell membranes suggests effects may also occur due to trace amines crossing lung membranes following inhalation. Effects due to inhaled trace amines entering the bloodstream have not previously been considered. Our initial studies indicate that blood glucose levels are altered in response to inhalation of some, but not all, trace amines. We have also confirmed that in the pancreas TAAR control insulin release. How TAAR do this, however, is unknown. ******To progress toward our long-term goal, and address the knowledge gaps identified above, the studies in this proposal will:***1) identify the transporters that control trace amine access to TAAR, ***2) determine the role of TAAR in adaptive responses to environmental stressors of different ecological origins, and ***3) determine the molecular mechanism of TAAR regulated insulin release. ******By filling these knowledge gaps new molecular targets for the regulation of trace amine function will be identified, which is crucial to elucidating the role of trace amine physiology in maintaining body functions. Identification of these targets will also be critical to future translational research by those investigating human disorders such as post-traumatic stress disorder, diabetes and obesity. Further, by determining the molecular basis of gender and species specific responses to chemicals associated with ecological hazards, some of which have life-or-death consequences, we will increase the understanding of adaptive stress responses in vertebrates, and the molecular basis of their physiological adaptations to habitat changes and ecological challenges.