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Hormonal Control of Calcium Metabolism

钙代谢的激素控制

基本信息

批准号：
10656301
负责人：
HENRY M. KRONENBERG
金额：
$ 205.41万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-08-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10656301
关键词：
Agonist Amino Acids Animal Model Antibodies Basic Science Biochemical CYP27B1 gene Cell Maturation Cells Cellular biology Chemicals Chromatography Chronic Kidney Failure Core Facility Development Disease Documentation Drug Kinetics Drug or chemical Tissue Distribution Evaluation Excretory function Family Funding Genetically Modified Animals Grant Hereditary Disease High Pressure Liquid Chromatography Homeostasis Hormonal Human Resources Hypoparathyroidism Investigation Ions Kidney Kidney Diseases Knowledge Ligand Binding Ligands Mass Spectrum Analysis Medical Metabolism Minerals Modality Molecular Molecular Conformation Molecular Probes Molecular and Cellular Biology Mus Occupational activity of managing finances Oral Osteoblasts Osteocytes Osteogenesis Osteoporosis PTH gene Peptides Performance Pharmacodynamics Phase I Clinical Trials Phenotype Phosphotransferases Preparation Procedures Productivity Prosthesis Protocols documentation Receptor Activation Regulation Research Research Design Research Personnel Research Project Grants Role Serum Signal Pathway Signal Transduction Tissues Training Transgenes Work absorption analog biosynthetic product bone bone cell bone mass bone metabolism calcium metabolism cellular targeting clinical development cost effective crosslink design improved in vivo inhibitor inorganic phosphate interest kidney cell kinase inhibitor novel peptidomimetics programs protein purification response salt-inducible kinase skeletal skeletal abnormality skeletal disorder skeletal stem cell small molecule stem cells synthetic peptide tool transgene expression translational applications translational potential urinary

项目摘要

Program Project "Hormonal Control of Calcium Metabolism" brings together a group of highly productive investigators who have worked closely together for a number of years supported by the project and other funded research grants. Tools of chemical molecular and cellular biology plus available carefully designed genetically modified animals are used to evaluate the role of parathyroid hormone in bone and renal cell biology. Several exciting medical translational applications have already come from this work and the potential for several more is evident. Project I (Gardella PI) Mechanisms of ligand binding and activation at the PTHR1 expands on earlier work that probes molecular details of ligand/receptor activation including newly available small molecule peptidomimetics as well as new chemical strategies to alter the pharmacokinetic and therefore ultimately pharmacodynamic of PTH analogs. Important translational implications from this work have been the discovery of a long-acting form of PTH for treatment of hypoparathyroidism soon to be entering phase 1 clinical trials and development of peptide negative agonists that show promise in animal models of controlling the multiple skeletal abnormalities seen in the hereditary disorder Jansen's disease. Project II (Kronenberg PI) PTH actions on cells of the osteoblast lineage builds on earlier progress with discovery of the first specific cellular target of PTH action the SIK kinases. This discovery opens a new field of important basic science investigation into the mode of action of PTH and has important translational implications in that the small molecule kinase inhibitors already discovered might ultimately lead to an orally active agent useful in the treatment of osteoporosis. Meantime these investigators continue to probe the effects of PTH on cellular targets of PTH action in bone from earliest precursors to mature osteoblasts and osteocytes. This work in addition to its fundamental interest could help with understanding how to improve PTH action since it is known that its effect wanes after continuous use for 12 months or less even though there are bone deficits remaining. Project III (Jueppner PI) renal regulation of phosphate homeostasis and its effects on bone deals with several recent novel findings. The first is importance of signal selectivity in PTH analogs in phosphate metabolism and bone cell maturation and secondly, the implications of high bone mass seen with skeletal transgenic expression of the Jansen's disease (JMC transgene) also studying a newly available specific inhibitor of NPT2A that may prove to be useful in hereditary disorders of hyperphosphatemia and CKD. Project IV (Mannstadt and Wein co-PI’s) The role of salt inducible kinases in renal PTH action builds on the recent discovery of the importance of the SIK kinase family in PTH bone action the investigators having demonstrated convincingly in preliminary work that SIK kinases are also critical to PTH actions on the kidney.

计划项目“钙代谢的激素控制”汇集了一批高度多年来一直密切合作的富有成效的研究人员，并得到了项目和其他资助的研究补助金。化学分子和细胞生物学工具加上使用精心设计的转基因动物来评估骨和肾细胞生物学中的甲状旁腺激素。几个令人兴奋的医学转化这项工作已经产生了一些应用，而且更多应用的潜力是显而易见的。项目 I (Gardella PI) PTHR1 的配体结合和激活机制扩展了早期研究探测配体/受体激活的分子细节的工作，包括新近可用的小分子分子肽模拟物以及改变药代动力学和的新化学策略因此最终是PTH类似物的药效学。由此产生的重要翻译意义我们的工作是尽快发现一种长效 PTH 来治疗甲状旁腺功能减退症即将进入一期临床试验并开发肽负激动剂动物模型有望控制遗传性多种骨骼异常詹森氏病。项目 II (Kronenberg PI) PTH 对成骨细胞的作用谱系建立在早期进展的基础上，发现了第一个 PTH 特定细胞靶标作用于 SIK 激酶。这一发现开辟了重要基础科学研究的新领域进入 PTH 的作用模式，并具有重要的转化意义，因为小已经发现的分子激酶抑制剂可能最终会产生口服活性剂可用于治疗骨质疏松症。与此同时，这些研究人员继续探索其影响从最早的前体细胞到成熟的成骨细胞，PTH 对骨中 PTH 作用的细胞靶标的影响骨细胞。这项工作除了其根本利益之外还可以帮助理解如何改善 PTH 作用，因为已知连续使用 12 个月后其效果会减弱，或即使仍然存在骨缺损，但仍较少。项目 III (Jueppner PI) 肾脏调节磷酸盐稳态及其对骨骼的影响涉及最近的一些新发现。第一个 PTH 类似物信号选择性在磷酸盐代谢和骨细胞成熟中的重要性其次，骨骼转基因表达对高骨量的影响詹森病（JMC 转基因）还研究了一种新的 NPT2A 特异性抑制剂，可能被证明对高磷血症和 CKD 等遗传性疾病有用。项目 IV（曼施塔特和 Wein co-PI’s）盐诱导激酶在肾 PTH 作用中的作用建立在最近的研究基础上研究人员发现 SIK 激酶家族在 PTH 骨作用中的重要性在初步工作中令人信服地证明 SIK 激酶对于 PTH 作用也至关重要肾脏。

项目成果

期刊论文数量（265）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A novel deletion involving the first GNAS exon encoding Gsα causes PHP1A without methylation changes at exon A/B.

DOI：
10.1016/j.bone.2022.116344
发表时间：
2022-04
期刊：
BONE
影响因子：
4.1
作者：
Campbell, Devon;Reyes, Monica;Kaygusuz, Sare Betul;Abali, Saygin;Guran, Tulay;Bereket, Abdullah;Kagami, Masayo;Turan, Serap;Juppner, Harald
通讯作者：
Juppner, Harald

Chondrocytes in the resting zone of the growth plate are maintained in a Wnt-inhibitory environment.

DOI：
10.7554/elife.64513
发表时间：
2021-07-26
期刊：
eLife
影响因子：
7.7
作者：
Hallett SA;Matsushita Y;Ono W;Sakagami N;Mizuhashi K;Tokavanich N;Nagata M;Zhou A;Hirai T;Kronenberg HM;Ono N
通讯作者：
Ono N

pHluorin2: an enhanced, ratiometric, pH-sensitive green florescent protein.