TBONE and phosphonates in mineralization during aging

TBONE 和膦酸盐在老化过程中矿化

基本信息

批准号：
8823713
负责人：
Timothy R Peterson
金额：
$ 11.53万
依托单位：
HARVARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8823713
关键词：
Address Adult Affect Aging Alendronate Apolipoprotein E Atherosclerosis Binding Biochemical Biological Assay Biological Process Biology Blood Vessels Bone remodeling Cells Deposition Diet Disease Dissection Dose Drug usage Estrogens Female Food Fosamax Gene Targeting Genes Genetic Genetic Screening Goals Haploid Cells Health Histology Human In Vitro Investigation Kidney Diseases Knockout Mice Light Lipoproteins Longevity Mediating Medicine Metastatic Neoplasm to the Bone Modeling Molecular Mus Mutant Strains Mice Mutation Names Osteoblasts Osteoclasts Osteoporosis Ovariectomy Pathway interactions Pharmaceutical Preparations Phenotype Physiologic calcification Physiological Physiology Play Population Process Proteins Research Resistance Role Structure Testing Therapeutic Therapeutic Effect Tissues Vascular Diseases Work age related base bisphosphonate bone bone aging bone cell bone loss cytotoxic gene discovery loss of function microbial microbial community microbiome mineralization mouse model novel novel therapeutic intervention osteoblast differentiation phosphonate response tumor progression

项目摘要

DESCRIPTION (provided by applicant): Mineralization is a process through which an organic substance becomes impregnated by inorganic substances. It is critically important to biology and when disrupted or hyperactivated contributes to wide- ranging effects on human health particularly in aging populations. For example, deficiencies in mineralization contribute to osteoporosis and cancer progression in bone, whereas elevated mineralization contributes to vascular disease such as atherosclerosis and kidney disease. The mechanism of action of the most commonly used drug class for treating several of these conditions, Nitrogenous Bisphosphonates (NBPs), is poorly understood. Through genetic screening in human haploid cells we identified several genes whose loss of function led to resistance to the cytotoxic effects of the NBP, Alendronate (Fosamax(R)), including a poorly characterized gene we named Target of BisphOsphonate NitrogEnous (heretofore TBONE). We show that TBONE is required both for biochemical responses triggered by NBPs as well as for bone function. Endogenous nitrogenous phosphonates (NPs), which are chemically related to NBPs and come from our diet and microbiome, potently regulate mineralization in bone-synthesizing osteoblasts in a TBONE-dependent manner. Lastly, TBONE deficient mice have low body mass, deregulated markers of bone remodeling and reduced lifespan. These findings suggest that phosphonates acting through TBONE are critical for tissue mineralization. In this proposal, we will test this hypothesi with the following aims: 1) Dissection of the mechanisms of TBONE-phosphonate molecular interactions; 2) Elucidation of the TBONE-phosphonate pathway in the bones and vasculature of mice. The identification of TBONE suggests an unexpected new understanding of and path of investigation for some of the most widely used medications, bisphosphonates. Additionally, that naturally occurring phosphonates stimulate mineralization suggests an important new determinant and safer therapeutic approach for numerous aging-associated conditions.

描述（由申请人提供）：矿化是一个过程，有机物质被无机物质浸渍。这对于生物学至关重要，而被破坏或过度激活的情况会导致对人类健康的广泛影响，尤其是在衰老人群中。例如，矿化的缺陷有助于骨骼的骨质疏松和癌症进展，而矿化升高则导致血管疾病，例如动脉粥样硬化和肾脏疾病。最常见的药物类别治疗这些疾病的作用机理，氮双膦酸盐（NBP）的作用机理知之甚少。通过人类单倍体细胞的遗传筛查，我们确定了几个基因，其功能丧失导致对细胞毒性作用的抗性 NBP，丙膦酸盐（fosamax（r）），包括一个特征较差的基因，我们将双膦酸盐氮的靶标（迄今TBONE）命名为靶标。我们表明，由NBP触发的生化反应以及骨功能都需要TBONE。内源性硝基磷酸盐（NP），与NBP化学相关，来自我们的饮食和微生物组，以TBONE依赖性方式在骨合成成骨细胞中有效调节矿化。最后，TBONE缺乏小鼠的体重低，骨重塑的放松标记和寿命降低。这些发现表明，通过TBONE作用的磷酸盐对于组织矿化至关重要。在此提案中，我们将以以下目的检验该假设：1）解剖Tbone-膦酸酯分子相互作用的机理； 2）在小鼠的骨骼和脉管系统中阐明TBON-磷酸途径。 TBONE的鉴定表明，对某些最广泛使用的双膦酸盐的药物对研究的新理解和研究路径。此外，天然存在的磷酸盐刺激矿化化表明，对于许多衰老相关的疾病，一种重要的新决定因素和更安全的治疗方法。