Physiology of Calcium Appetite

描述（由申请人提供）：低自愿钙摄入量与困扰美国人口的几种疾病有关，包括骨质疏松症、高血压、肥胖症和经前综合征。但是，尽管有许多增加钙摄入量的建议，但几乎没有研究来了解为什么钙摄入量如此之低。该项目将通过识别和描述一些生理和遗传控制来解决这个问题，这些控制是钙消耗的基础。在这次更新申请中提出了两个目标。首先是确定负责钙消耗的基因。在目标1.1中，将培育同源和同源小鼠，以分离含有消耗相关基因的小染色体片段。在目标1.2中，将使用计算机模拟方法和基因表达研究的组合评估每个片段中的候选基因。第二个目标是表征该项目已经涉及控制钙消耗的两个基因的作用模式和位点;钙敏感受体Casr和甜味受体Tas 1 r3。这将通过比较避免钙的小鼠品系（C57 BL/6 J或B6品系）与贪婪地饮用钙的品系（PWK/PhJ或PWK品系）的受体活性来完成。该计划是使用HEK细胞表达系统来比较CaSR和T1 R3的B6和PWK形式的生理反应（目的2.1）、原位杂交、实时PCR和免疫化学来表征B6和PWK形式的CaSR和T1 R3在味觉组织中的表达（目标2.2），和味觉电生理学，以确定两种菌株在生理反应或CaSR和T1 R3的位置方面的任何差异的功能意义（目的2.3）。目标1将导致发现参与调节钙摄入和代谢的基因。目的2将测试一个或一对特定的受体改变钙味的可能性。了解钙感知的机制是回答为什么钙摄入量如此低的问题的重要一步。考虑到小鼠和人类基因组之间的许多相似性，在小鼠中进行的此类研究将与控制人类的钙消耗直接相关，从而与钙摄入过量或不足相关的许多疾病直接相关。公共卫生相关性：该项目调查了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、高血压和经前综合征。了解钙的消耗是如何控制的，将有助于制定有效的策略和治疗方法，以增加钙的摄入量，从而降低这些钙相关疾病的发病率。

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.