PTH Inverse Agonists as Therapy for Jansen’s Disease

PTH 反向激动剂治疗詹森病

• 批准号: 10200028
• 负责人: THOMAS J GARDELLA
• 金额: $ 40.27万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10200028
• 关键词: Adult; Affect; Agonist; Alleles; Amino Acids; Arrestins; Binding; Bone Growth; Bone Resorption; Bone plates; Cartilage; Cell Line; Cells; Cellular Assay; Child; Childhood; Chondrocytes; Chronic; Chronic Kidney Failure; Collagen Type I; Collagen Type II; Confocal Microscopy; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Deformity; Development; Differentiation and Growth; Disease; Distal; Documentation; Dose; Drug Kinetics; Dwarfism; Elderly; End stage renal failure; Epiphysial cartilage; Fluorescence Resonance Energy Transfer; G-Protein-Coupled Receptors; GTP-Binding Proteins; Genetic Status; Growth; Homeostasis; Hybrids; Hypercalcemia; In Vitro; Infusion procedures; Injections; Ions; Kidney; Knock-in; Lead; Length; Life; Ligands; Metabolism; Metaphyseal chondrodysplasia; Methods; Minerals; Modeling; Molecular; Molecular Target; Mus; Mutagenesis; Mutation; Nephrocalcinosis; Osteoblasts; Osteogenesis; PTH gene; Parathyroid Hormone Receptor; Patients; Peptides; Pharmacodynamics; Phenotype; Physiology; Play; Proliferating; Property; Rare Diseases; Receptor Activation; Regulation; Renal Replacement Therapy; Reporter; Role; Secondary Hyperparathyroidism; Serum; Signal Pathway; Signal Transduction; Skeletal Development; Structure; Testing; Therapeutic; Tissues; Transgenes; Transgenic Mice; Transgenic Organisms; Transmembrane Domain; Variant; Vertebral column; base; bone; bone loss; bone metabolism; bone turnover; cortical bone; developmental disease; effective therapy; experimental study; gain of function mutation; hormone analog; hypercalciuria; improved; in vitro Assay; in vivo; insight; mouse model; mutant; novel; parathyroid hormone-related protein; peptide analog; pharmacokinetics and pharmacodynamics; prevent; promoter; skeletal; skeletal abnormality; small molecule; sorting nexins

PROJECT SUMMARY/ABSTRACT Jansen's Metaphyseal Chondrodysplasia (JMC) is a rare developmental disease caused by activating, gain- of-function mutations in the PTH1R, the receptor for parathyroid hormone (PTH) and PTH-related peptide (PTHrP). The PTH1R mutations lead to abnormal skeletal development resulting in severe, crippling bone deformities, and extremely short stature. In addition, JMC patients develop chronic, often severe hypercalcemia and hypercalciuria that contribute to development of chronic kidney disease (CKD) later in life, necessitating kidney replacement therapy in older adults. There is currently no cure or effective treatment for JMC, despite a clearly defined molecular target. We previously developed several PTH-PTHrP analogs that show inverse agonism when tested in cells expressing different constitutively active PTH1Rs, including the H223R-PTH1R mutant. Our extensive preliminary studies have shown that one inverse agonist, namely L11,dW12,W23,Y36-PTHrP(7-36) (dTrp12-PTHrP(7-36)), reverses in vivo effects induced by the H223R-PTH1R mutant expressed via the type I collagen promoter (Col1-H223R mice), thus reducing bone turnover and cortical bone loss, and improving bone length. We now plan to provide further documentation that this PTH analog, or a derivative thereof, can prevent the growth plate abnormalities, which occur in mice expressing the H223R-PTH1R mutant in proliferating chondrocytes via the type II collagen promoter (Col2-H223R mice); homozygous Col2-H223R mice are small, just like JMC patients, and it is plausible that pre- and/or post-natal treatment with an inverse agonist will improve bone growth. We also propose developing transgenic mice expressing the mutant PTH1R in proximal and distal tubules, and if necessary a “knock-in” JMC mouse, i.e. a murine model mimicking all disease aspects. Besides correction of growth plate abnormalities in children affected by JMC, it is conceivable that inverse agonists will prevent hypercalcemia and hypercalciuria in pediatric and adult patients with activating PTH1R mutations, and thus nephrocalcinosis and CKD. Insights into the mechanisms that reduce signaling at the mutant PTH1R may lead to effective approaches targeting the wild-type PTH1R through additional peptide analogs or small molecules in patients with PTH- or PTHrP- dependent hypercalcemia, or with secondary hyperparathyroidism due to CKD. In addition, our studies will provide novel insights into growth plate, bone, and kidney physiology, and they will encourage searches for inverse agonists at other disease-causing G protein-coupled receptor mutants.

项目摘要/摘要 詹森软骨发育不良症(JMC)是一种罕见的发育性疾病，由激活、获得、释放和释放引起。 甲状旁腺激素受体PTH1R及其相关多肽的功能缺失突变 (PTHrP)。PTH1R突变导致骨骼发育异常，导致严重的骨骼残疾 畸形，和极矮的身材。此外，JMC患者会发展成慢性的，通常是严重的 高钙血症和高钙尿症会在晚年导致慢性肾脏疾病(CKD)的发展， 有必要对老年人进行肾脏替代治疗。目前还没有治愈或有效的治疗方法 JMC，尽管有明确的分子靶点。我们之前开发了几个PTH-PTHrP类似物 当在表达不同成分活性的PTH1R的细胞中测试时，显示出反向激动性，包括 H223R-PTH1R突变体。我们广泛的初步研究表明，有一种反向激动剂，即 L11、DW12、W23、Y36-PTHrP(7-36)(dTrp12-PTHrP(7-36))逆转H223R-PTH1R的体内效应 通过I型胶原启动子(COL1-H223R小鼠)表达的突变体，从而降低骨转换和 皮质骨质流失，改善骨骼长度。我们现在计划提供进一步的文档，说明此PTH 类似物或其衍生物可以防止生长板异常，这种异常发生在小鼠的表达 通过II型胶原启动子促进软骨细胞增殖的H2 23R-PTH1R突变体(COL2-H2 23R小鼠)； 纯合子COL2-H223R小鼠和JMC患者一样很小，出生前和/或出生后 使用反向激动剂治疗将促进骨骼生长。我们还建议开发转基因小鼠 在近端和远端小管中表达突变的PTH1R，如有必要，还可以表达“敲入”的JMC小鼠，即 模拟所有疾病方面的小鼠模型。除矫正儿童生长板异常外 受JMC影响，可想而知，反向激动剂将预防高钙血症和高钙尿。 儿童和成人患者激活PTH1R突变，从而导致肾钙质沉着症和CKD。真知灼见 深入研究减少突变PTH1R信号的机制可能会导致有效的靶向方法 甲状旁腺激素或甲状旁腺激素受体患者的野生型甲状旁腺激素受体 依赖性高钙血症，或因慢性肾脏病继发性甲状旁腺功能亢进症。此外，我们的研究将 提供对生长板、骨骼和肾脏生理学的新见解，他们将鼓励搜索 其他致病G蛋白偶联受体突变体的反向激动剂。