Physiology of Calcium Appetite

钙食欲的生理学

• 批准号: 8015407
• 负责人: MICHAEL G TORDOFF
• 金额: $ 9.97万
• 依托单位: MONELL CHEMICAL SENSES CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-22 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8015407
• 关键词: Address; Agonist; Behavioral; Brain; Breeding; Calcium; Calcium-Sensing Receptors; Candidate Disease Gene; Code; Computer Simulation; Congenic Strain; Consumption; Desire for food; Development; Dimerization; Disease; Electrophysiology (science); Embryo; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genetic Polymorphism; Genome; Homeostasis; Human; Human Genome; Hypertension; Immunochemistry; Immunohistochemistry; In Situ Hybridization; Incidence; Ingestion; Lead; Link; Location; Magnesium; Methods; Minerals; Molecular Conformation; Mouse Strains; Mus; Obesity; Osteoporosis; Perception; Physiological; Physiology; Population; Premenstrual syndrome; Production; Proteins; Quantitative Trait Loci; Receptor Gene; Recommendation; Research; Saccharin; Signal Transduction; Site; Solutions; System; Taste Perception; Testing; Time; Tissues; Work; calcium intake; calcium metabolism; congenic; consomic; drinking; gene discovery; kidney cell; novel; preference; public health relevance; receptor; response; sweet receptor; sweet taste perception; treatment strategy

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.

描述（由申请人提供）：低自愿性钙摄入量与几种疾病有关，这些疾病困扰着美国人群，包括骨质疏松症，高血压，肥胖和经前综合征。但是，尽管有很多建议增加钙摄入量，但几乎没有研究了解为什么钙摄入量如此之低。该项目将通过识别和表征钙消耗量的一些生理和遗传控制来解决这个问题。在此续签应用中提出了两个目标。首先是确定负责消耗钙的基因。在AIM 1.1中，将繁殖先天小鼠和综合小鼠，以分离包含与消费相关基因的小染色体片段。在AIM 1.2中，将使用硅方法和基因表达研究的组合评估每个片段中的候选基因。第二个目的是表征该项目已经与钙消耗控制有关的两个基因的模式和作用位点；钙感应受体CASR和甜味受体TAS1R3。这将通过比较避免钙（C57BL/6J或B6菌株）的小鼠菌株的受体活性与狂热的钙（PWK/PHJ或PWK菌株）。该计划是使用HEK细胞表达系统比较CASR和T1R3的B6和PWK形式的生理反应（AIM 2.1），原位杂交，实时PCR和免疫化学表征B6和PWK形式的表达CASR和PWK形式的CASR和T1R3在味觉2.2中的功能（目标2 2.2），以及良好的型号（目标），以及良好的元素，以及良好的电子学，以及良好的电子学，以及良好的电子元素，这些型号的态度是实现的。在CASR和T1R3的生理反应或位置（AIM 2.3）。 AIM 1将导致发现与调节钙的摄入和代谢有关的基因。 AIM 2将测试特定受体或成对受体转导钙味的可能性。了解钙感知的基础机制是回答为什么钙摄入量如此之低的问题的重要步骤。鉴于小鼠和人类基因组之间的许多相似之处，在小鼠中，此类研究将与人类控制钙消耗的直接相关，因此与钙摄入过量或不足有关的许多疾病。公共卫生相关性：该项目研究了钙摄入和偏好的生理和遗传控制。低钙摄入量与多种疾病有关，包括骨质疏松症，高血压和经前综合征。了解如何控制钙的消耗将导致开发有效的策略和治疗方法，以增加钙的摄入量，从而减少这些相关疾病的发生率。