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.

抽象的骨质疏松症和低骨骼质量（骨质减少）估计会影响55％的美国人群超过50岁；总共超过5000万人，对患者的生活质量产生了重大影响。这当前用于骨质疏松症的标准治疗方法是给药含氮的双膦酸盐（NBPS）。但是，这些高电荷药物进入，通过交通并到达分子的机制靶标细胞尚不清楚靶细胞。该提议的长期目标是解构 NBP反应必不可少的分子途径。为此，我们将以初步的遗传研究为基础使用细胞测定和小鼠模型，以及体外结合和功能测定 NBP与我们确定的目标之间的相互作用。我们以前的工作利用了两个不同的高通量全基因组筛选以识别NBPS作用所需的200多个基因。我们的最初重点研究一直在两个基因的作用，即Atraid和Slc37a3的作用，这些基因强烈影响对NBP的反应，这些药物的内吞运输可能是必需的。该提议以我为基础剖析Atraid和SLC37A3如何促进NBP运输及其细胞功能，ii）研究 GWA与BMD变化相关的两个转录因子，当耗尽时可能会感知细胞到 NBP和iii）使用有条件的Atraid基因敲除小鼠，研究的机制这些药物是骨转移的治疗性。这些研究在一起产生了更广泛的了解 NBP用来影响细胞和组织的分子途径。该建议重点介绍了一部分基因，并将为未来的工作奠定阶段，以确定药物筛选中鉴定的基因如何预测患者对NBP的反应，包括治疗的有效性，所需的NBP剂量以及不良副作用。此外，这种重点是理解廉价，常规药物的机制为骨质疏松症的治疗策略的发展带来新的观点和假设。