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The role of salt inducible kinases in renal PTH action

盐诱导激酶在肾 PTH 作用中的作用

基本信息

批准号：
10207599
负责人：
Michael Mannstadt
金额：
$ 41.09万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10207599
关键词：
3-Dimensional Acute Adaptor Signaling Protein Adenine Autoimmune Binding Biology Blood Bone Diseases Bone Resorption Bypass CYP27B1 gene Calcium Cells Chronic Chronic Kidney Failure Cyclic AMP Cyclic AMP-Dependent Protein Kinases Data Diet Disease Endocrine Enzymes Epithelial Cells Event Excretory function Family Family member Future Gene Expression Genes Genetic Transcription Goals Homeostasis Hormonal Hormone Responsive Hormone use Hormones Human In Vitro Inflammatory Injury to Kidney Inorganic Phosphate Transporter Ions Kidney Kidney Diseases Knock-out Knowledge Light Link Mediating Mediator of activation protein Metabolism Minerals Mission Modeling Modification Molecular Mus National Institute of Diabetes and Digestive and Kidney Diseases Nephrons Nucleic Acid Regulatory Sequences Oral Organ Organoids Osteocytes Osteogenesis Osteoporosis PTH gene Parathyroid Hormone Receptor Pathway interactions Pharmaceutical Preparations Phenotype Phosphoric Monoester Hydrolases Phosphorylation Phosphorylation Inhibition Play Post-Translational Regulation Production Protein Isoforms Protein Phosphatase 2A Regulatory Subunit PR53 Proteins Proximal Kidney Tubules Receptor Activation Regulation Regulatory Pathway Research Role Serum Signal Pathway Signal Transduction Testing Therapeutic Therapeutic Uses Tissues Transcriptional Activation United States National Institutes of Health Upstream Enhancer Vitamin D bone bone health bone mass brush border membrane calcium metabolism chromatin immunoprecipitation experimental study hormonal signals hormone resistance human disease in vivo inhibitor/antagonist inorganic phosphate kidney cell kinase inhibitor mouse model novel novel strategies novel therapeutic intervention receptor renal epithelium salt-inducible kinase skeletal skeletal disorder small molecule small molecule inhibitor therapeutic target transcription factor transcriptome transcriptome sequencing treatment effect uptake urinary

项目摘要

Project Summary Parathyroid hormone (PTH) maintains mineral ion homeostasis by interacting with the PTH/PTHrP receptor to induce transcriptional and post-transcriptional modifications in target tissues. PTH stimulates resorption of the mineral matrix in bone, and increases production of active vitamin D, calcium reabsorption, and phosphate excretion in the kidneys. Despite the central role of PTH as a regulatory hormone, many of the downstream intracellular target molecules that orchestrate PTH signaling events have yet to be identified. Characterization of these pathways will expand current knowledge of the mechanisms governing mineral homeostasis, and suggest new therapeutic strategies to counteract or restore PTH action in skeletal and renal disease. Recently, salt- inducible kinases (SIKs) were identified as intracellular mediators of PTH signaling in osteocytes, and small- molecule inhibitors of SIKs were found to mimic PTH action on bone in vivo. The objective of this proposal is to explore whether analogous SIK-dependent PTH signaling pathways are active in the kidney. Aim 1 of this proposal will explore the molecular mechanisms through which PTH/SIK signaling regulates CYP27B1 expression. In renal cells, human kidney organoids, and mice, both PTH and the SIK inhibitor YKL-05-099 increase expression of CYP27B1, the enzyme that converts inactive vitamin D to its active form. In renal cells, PTH treatment results in decreased phosphorylation of SIK3 substrate CRTC2. The remaining intermediaries of the PTH/SIK/CYP27B1 pathway will be characterized using in vitro experiments targeting molecules upstream and downstream of SIK in renal cells and organoids. Chromatin Immunoprecipitation of CRTC family members will identify the regulatory regions necessary for CYP27B1 transcriptional activation by PTH/SIK. Aim 2 will define the role of PTH/SIK signaling in renal phosphate reabsorption. Mice treated with PTH or YKL-05-099 have decreased serum phosphate levels, and YKL-05-099 treatment decreases phosphate transporter Npt2a localization to the renal brush border membrane. These mice will be tested to confirm that SIK inhibition induces phosphaturia in vivo. Three SIK family members will be knocked out in renal epithelial cells and their effect on phosphate uptake assessed. Aim 3 will characterize the phenotype of mice lacking renal SIK1 and SIK3, and explore the therapeutic potential of small molecule SIK inhibitors in CKD-MBD. The experiments described here explore a novel role for SIKs in regulating PTH signaling in the kidney. In addition, mouse models developed for this project will help to shed light on the crucial bone/kidney regulatory axis that controls mineral homeostasis and bone health. This project also offers a novel application for SIK inhibitors, a class of drug currently studied for their application in autoimmune and other inflammatory disorders, as treatment in later stages of chronic kidney disease (CKD) and other disorders of mineral ion homeostasis that are unresponsive to PTH.

项目总结