Deciphering Mechanisms of Nitrogen-Containing Bisphosphonates - Admin Supplement

破译含氮双膦酸盐的机制 - 管理补充

基本信息

批准号：
10732846
负责人：
Lauren Elizabeth Surface
金额：
$ 7.8万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10732846
关键词：
Affect Age American Binding Biological Assay Bone Density Bone Diseases Bone Growth Bone necrosis CRISPR interference Cell Lineage Cell physiology Cells Cellular Assay Charge Cytosol Drug Prescriptions Drug Screening Epigenetic Process Femoral Fractures Fright Future Genes Genetic Screening Genetic Transcription Genetic study Goals Impairment In Vitro Individual Investigation Jaw Kidney Knock-out Knockout Mice Macrophage Mediating Metastatic Neoplasm to the Bone Modeling Molecular Molecular Target Mus NFIC gene Nitrogen Osteopenia Osteoporosis Ovariectomy Pathway interactions Patients Persons Pharmaceutical Preparations Population Process Proteins Quality of life Resistance Risk Role Skeletal system Therapeutic Time Tissues Toxic effect Treatment Efficacy Treatment Side Effects Tumor-associated macrophages Wild Type Mouse Work bisphosphonate bone bone loss bone mass cell type conditional knockout dosage drug mechanism genome wide association study genome wide screen interest mouse model patient population patient response prevent response side effect single-cell RNA sequencing standard care therapy development tool trafficking transcription factor treatment strategy

项目摘要

Abstract Osteoporosis and low bone mass (osteopenia) are estimated to affect 55 percent of the American population over the age of 50; over 50 million people in total, with major consequences for the patients’ quality of life. The current standard treatment for osteoporosis is administration of nitrogen-containing bisphosphonates (NBPs). However, the mechanism by which these highly-charged drugs enter, traffic through, and reach their molecular targets and effect target cells is poorly understood. The long-term goal of this proposal is to deconstruct the molecular pathways essential for NBP response. To do this, we will build upon preliminary genetic studies by using cell assays and mouse models, as well as in vitro binding and functional assays to explore the interactions between NBPs and our identified targets. Our previous work utilized two distinct high-throughput genome-wide screens to identify over 200 genes required for the action of NBPs. The initial focus of our studies has been on the role of two genes, ATRAID and SLC37A3, that strongly affect the response to NBPs, and are likely to be required for the endocytic trafficking of these drugs. This proposal builds upon this to i) dissect how ATRAID and SLC37A3 facilitate NBP trafficking and their cellular function, ii) investigate the role of two transcription factors, associated by GWAS with changes in BMD, that when depleted may sensitize cells to the effects of NBPs, and iii) using conditional ATRAID knockout mice, investigate the mechanism by which these drugs are therapeutic for bone metastases. Together, these studies generate a broader picture of the molecular pathways that NBPs use to affect cells and tissues. This proposal focuses on a subset of identified genes, and will set the stage for future work determining how genes identified in drug screens may predict patient response to NBPs, including efficacy of treatment, dosage of NBPs needed, and adverse side effects. Moreover, this focus on understanding the mechanisms of an inexpensive, commonly prescribed drug will bring new perspectives and hypotheses to the development of treatment strategies for osteoporosis.

抽象的据估计，骨质疏松症和低骨量（骨质减少）影响着 55% 的美国人口 50岁以上；总计超过5000万人，对患者的生活质量产生重大影响。目前骨质疏松症的标准治疗是给予含氮双膦酸盐（NBP）。然而，这些高电荷药物进入、运输和到达其分子的机制对目标和效应靶细胞知之甚少。该提案的长期目标是解构 NBP 反应所必需的分子途径为此，我们将基于初步的遗传学研究。使用细胞测定和小鼠模型以及体外结合和功能测定来探索 NBP 和我们确定的目标之间的相互作用我们之前的工作利用了两种不同的高通量。全基因组筛选，以确定 NBP 发挥作用所需的 200 多个基因，这是我们最初的重点。研究针对两个基因 ATRAID 和 SLC37A3 的作用，它们强烈影响对 NBP 的反应，并且可能是这些药物的内吞贩运所必需的。该提案以此为基础 i) 剖析 ATRAID 和 SLC37A3 如何促进 NBP 运输及其细胞功能，ii) 研究两种转录因子，通过 GWAS 与 BMD 变化相关，当它们耗尽时，可能会使细胞对 NBP 的影响，以及 iii) 使用条件 ATRAID 敲除小鼠，研究其机制这些药物可以治疗骨转移，这些研究共同为骨转移提供了更广阔的前景。 NBP 用于影响细胞和组织的分子途径该提案重点关注已确定的一部分。基因，并将为未来的工作奠定基础，确定药物筛选中识别的基因如何预测患者对 NBP 的反应，包括治疗剂量的功效、所需的 NBP 以及不良副作用。此外，这种对了解廉价、常用处方药物机制的关注将有助于为骨质疏松症治疗策略的制定带来新的视角和假设。