Physiology of Calcium Appetite

描述(由申请人提供)：自愿低钙摄入量与几种折磨美国人的疾病有关，包括骨质疏松症、高血压、肥胖症和经前综合症。但是，尽管有许多建议增加钙的摄入量，但几乎没有研究能理解为什么钙的摄入量如此之低。这个项目将通过确定和描述钙消费背后的一些生理和遗传控制来解决这个问题。在这次续签申请中提出了两个目标。首先是确定与钙的消耗有关的基因。在目标1.1中，将培育同源和共生小鼠，以分离包含消费相关基因的小染色体片段。在Aim 1.2中，每个片段中的候选基因将使用计算机方法和基因表达研究相结合的方法进行评估。第二个目的是描述两个基因的作用模式和作用部位，这两个基因是：钙敏感受体CaSR和甜味受体Tas1r3，这两个基因已经被该项目涉及到控制钙消耗。这将通过比较不吃钙的小鼠品系(C57BL/6J或B6品系)和狂饮钙的品系(PWK/PhJ或PWK品系)的受体活性来完成。该计划是利用HEK细胞表达系统比较B6和PWK形式的CaSR和T1R3的生理反应(目标2.1)，原位杂交，实时荧光聚合酶链式反应和免疫化学表征B6和PWK形式的CaSR和T1R3在味觉组织中的表达(目标2.2)，以及味觉电生理学，以确定两种菌株之间在CASR和T1R3的生理反应或位置上的任何差异的功能意义(目标2.3)。目标1将导致发现与调节钙的摄入和代谢有关的基因。目标2将测试特定受体或一对受体转导钙味觉的可能性。了解钙感知的机制是回答为什么钙摄入量如此低这一问题的重要一步。鉴于老鼠和人类基因组之间的许多相似之处，在老鼠身上进行的这种研究将与控制人类的钙消耗直接相关，从而控制与钙摄入量过高或不足有关的许多疾病。公共卫生相关性：该项目调查钙摄入量和偏好的生理和遗传控制。低钙摄入与几种疾病有关，包括骨质疏松症、高血压和经前综合症。了解如何控制钙的消耗将导致制定有效的策略和治疗方法，以增加钙的摄入量，从而减少这些与钙有关的疾病的发生率。

DESCRIPTION (provided by applicant): Low voluntary calcium intakes have been implicated in several diseases that afflict the U.S. population including osteoporosis, hypertension, obesity, and premenstrual syndrome. But despite many recommendations to increase calcium intake there has been almost no research to understand why calcium intakes are so low. This project will address this question by identifying and characterizing some of the physiological and genetic controls that underlie calcium consumption. Two aims are proposed in this renewal application. The first is to identify genes responsible for the consumption of calcium. In Aim 1.1, congenic and consomic mice will be bred in order to isolate small chromosomal fragments containing consumption-related genes. In Aim 1.2, candidate genes in each fragment will be assessed using a combination of in silico methods and gene expression studies. The second aim is to characterize the modes and sites of action of two genes that this project has already implicated in the control of calcium consumption; the calcium-sensing receptor, Casr, and the sweet taste receptor, Tas1r3. This will be done by comparing the receptor activity of a mouse strain that avoids calcium (the C57BL/6J or B6 strain) with a strain that drinks calcium avidly (the PWK/PhJ or PWK strain). The plan is to use an HEK cell expression system to compare the physiological responses of B6 and PWK forms of CaSR and T1R3 (Aim 2.1), in situ hybridization, real-time PCR, and immunochemistry to characterize the expression of the B6 and PWK forms of CaSR and T1R3 in taste tissue (Aim 2.2), and gustatory electrophysiology to determine the functional significance of any differences between the two strains in physiological response or location of CaSR and T1R3 (Aim 2.3). Aim 1 will lead to the discovery of genes involved in regulating the ingestion and metabolism of calcium. Aim 2 will test the possibility that a specific receptor or pair of receptors transduce calcium taste. Understanding the mechanisms underlying calcium perception is an important step toward answering the question of why calcium intakes are so low. Given the many similarities between the mouse and human genome, such studies in mice will have direct relevance for the control of calcium consumption by humans, and thus the many diseases associated with excess or insufficient calcium intake. PUBLIC HEALTH RELEVANCE: This project investigates the physiological and genetic controls of calcium intake and preference. Low calcium intakes are associated with several diseases including osteoporosis, hypertension and premenstrual syndrome. An understanding of how calcium consumption is controlled will lead to the development of effective strategies and treatments to increase calcium intake and thus reduce the incidence of these calcium- related diseases.