CA2+-RECEPTOR: IMMUNE MODULATION IN VIVO AND IN VITRO

CA2 受体：体内和体外免疫调节

• 批准号: 7216768
• 负责人: Edward M Brown
• 金额: $ 29.75万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7216768
• 关键词: Address; Animal Model; Antibodies; Autoimmune Process; Autoimmunity; Binding; Biochemical; Calcium; Calcium-Sensing Receptors; Cell Surface Receptors; Cell surface; Compatible; Complement; Condition; Defect; Development; Diagnosis; Disease; Endocrine System Diseases; Excision; Extracellular Domain; Fc Receptor; GTP-Binding Proteins; Goals; Graves' Disease; Homeostasis; Hypercalcemia; Hyperparathyroidism; Hypocalcemia result; Hypoparathyroidism; Hypothyroidism; Immunization; In Vitro; Individual; Ions; Mediating; Medical; Minerals; Mutation; Numbers; Parathyroid Adenoma; Pathway interactions; Patients; Persons; Physiological; Play; Prevalence; Role; base; cytotoxicity; extracellular; immunoregulation; in vivo; receptor

DESCRIPTION (provided by applicant): Autoimmunity is the cause of several common endocrine disorders. Graves' disease and nongoitrous hypothyroidism are examples of diseases caused by activating and inhibitory antibodies, respectively, to a G protein-coupled cell surface receptor (GPCR). The extracellular calcium-sensing receptor (CaR) is a GPCR that plays a crucial role in maintaining mineral ion homeostasis by virtue of its capacity to sense small changes in the extracellular ionized calcium concentration (Ca2+o). The physiological relevance of the CaR was established by the discovery of patients with activating or inactivating mutations that produce hypo- or hypercalcemic conditions, respectively. The former is termed autosomal dominant hypocalcemia (ADH) and the latter familial hypocalciuric hypercalcemia (FHH). Similar to inactivating or activating mutations, there might be patients with inactivating or activating antibodies to the CaR. Indeed, we recently described 4 patients with inactivating antibodies to the CaR, three of whom had a picture of FHH while one had biochemical findings more like primary hyperparathyroidism (PHPT). Surprisingly, further preliminary studies have identified inactivating antibodies in two individuals who had undergone removal of a parathyroid (PT) adenoma for a diagnosis of PHPT, raising the possibility that anti-CaR antibodies can contribute to the development of PHPT in a subset of patients. Additional preliminary studies have also identified two hypocalcemic individuals with activating antibodies to the receptor, who have a biochemical picture compatible with hypoparathyroidism. The overall goal of this proposal is to document that activating and inactivating CaR antibodies can cause forms of hypoparathyroidism and PTH-dependent hypercalcemia, respectively, that should be distinguished from other causes of these disorders and may be amenable to specific CaR-based medical therapy. The following aims are addressed at achieving this goal: (1) To identify and characterize inactivating antibodies to the CaR in persons with PTH-dependent hypercalcemia. (2) To identify and characterize activating antibodies to the CaR in persons with hypoparathyroidism. (3) To develop an animal model of activating and/or inactivating antibodies by immunization with the CaR's extracellular domain.

描述（由申请人提供）：自身免疫是几种常见内分泌失调的原因。格雷夫斯病和非甲状腺肿性甲状腺功能减退症是分别由 G 蛋白偶联细胞表面受体 (GPCR) 的激活性抗体和抑制性抗体引起的疾病的例子。细胞外钙敏感受体 (CaR) 是一种 GPCR，由于其能够感知细胞外离子钙浓度 (Ca2+o) 的微小变化，因此在维持矿物质离子稳态中发挥着至关重要的作用。 CaR 的生理相关性是通过发现具有分别产生低钙血症或高钙血症的激活或失活突变的患者来确定的。前者称为常染色体显性低钙血症（ADH），后者称为家族性低钙尿性高钙血症（FHH）。与失活或激活突变类似，可能存在具有 CaR 失活或激活抗体的患者。事实上，我们最近描述了 4 名患有 CaR 失活抗体的患者，其中 3 名患者出现了 FHH，而一名患者的生化结果更像是原发性甲状旁腺功能亢进症 (PHPT)。令人惊讶的是，进一步的初步研究在两名因诊断 PHPT 而接受甲状旁腺 (PT) 腺瘤切除的个体中发现了灭活抗体，这提高了抗 CaR 抗体可能有助于部分患者发生 PHPT 的可能性。其他初步研究还确定了两名低钙血症患者具有该受体的激活抗体，他们的生化特征与甲状旁腺功能减退症相符。该提案的总体目标是证明激活和灭活 CaR 抗体可分别导致甲状旁腺功能减退症和 PTH 依赖性高钙血症，应将其与这些疾病的其他原因区分开来，并且可能适合基于 CaR 的特定药物治疗。为了实现这一目标，我们提出了以下目标：(1) 鉴定和表征 PTH 依赖性高钙血症患者体内的 CaR 失活抗体。 (2) 鉴定并表征甲状旁腺功能减退症患者体内 CaR 的激活抗体。 (3)建立通过CaR胞外结构域免疫来激活和/或灭活抗体的动物模型。

项目成果

Mapping of human autoantibody binding sites on the calcium-sensing receptor.

• DOI: 10.1359/jbmr.090703
• 发表时间: 2010-01
• 期刊: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
• 作者: Kemp EH;Gavalas NG;Akhtar S;Krohn KJ;Pallais JC;Brown EM;Watson PF;Weetman AP
• 通讯作者: Weetman AP