Polycystins/TAZ as a novel therapeutic target to treat osteoporosis

多囊蛋白/TAZ作为治疗骨质疏松症的新靶点

基本信息

批准号：
10194039
负责人：
L DARRYL QUARLES
金额：
$ 38万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10194039
关键词：
Address Adipocytes Adipose tissue Anabolic Agents Bone Formation Inhibition Bone Marrow Bone Resorption Bone Surface C-terminal Chemicals Complex Computational Biology Cues Defect Disease Drug Kinetics Fatty acid glycerol esters Genetic Goals Grant Health Human Lead Maintenance Marrow Mediating Mesenchymal Stem Cells Molecular Mus Osteoblasts Osteoclasts Osteocytes Osteogenesis Osteopenia Osteoporosis Outcome PKD2 protein PPAR gamma Pathogenesis Pathogenicity Pathologic Pharmaceutical Preparations Pharmacology Phase Phenotype Play Process Property Regulation Role Safety Signal Transduction Testing Therapeutic Transcriptional Coactivator with PDZ-Binding Motif Validation Vision analog bone bone disuse atrophy bone loss bone mass defined contribution design genetic approach high reward high risk in vivo innovation lead optimization lipid biosynthesis mechanical load mechanotransduction mouse genetics mouse model new therapeutic target novel novel strategies novel therapeutics osteoblast differentiation paracrine polycystic kidney disease 1 protein pre-clinical prevent small molecule stem cell differentiation supercomputer therapeutic lead compound therapeutic target tool transdifferentiation

项目摘要

Osteoblasts (Obs) differentiate from mesenchymal stem cells (MSCs) and polarize on bone surfaces to produce new bone that fills in cavities created by osteoclast-mediated bone resorption. Polycystins 1 and 2 (Pkd1/Pkd2) and TAZ form a mechanosening complex in mature Obs that plays an important role in the maintenance of bone mass. Genetic loss of Pkd1/TAZ in mature Obs of mice results in osteopenia caused by decreased Ob-mediated bone formation (Ob-BF) and an unexpected increase in bone marrow fat (MAT). This inverse relationship between Ob-BF and marrow adipocytes in compound Pkd1/TAZ deficient mice resembles certain forms of human osteoporosis (OP). Increased MAT in OP is thought to be due to a shift of MSC differentiation to adipocytes at the expense of Obs, and the release of paracrine factors by adipocytes are purported to inhibit Ob- BF. However, increased MAT resulting from disruption of Pkd1/TAZ in mature Ob is not readily explained by effects on lineage commitment. Rather, the direct effects of Pkd1/TAZ in Obs raises the possibility that other mechanisms are responsible for converting Obs to adipocytes. An unexplored possibility is that adipocytes arise from transdifferentiation of Obs. We propose the novel hypothesis that physical forces in the bone microenvironment regulate Ob transdifferentiation to adipocytes (OAT) through activation of Pkd1/Pkd2/TAZ. The R61 phase will: 1) explore the mechanisms whereby Pkd1/Pkd2/TAZ in Obs inversely regulate Ob-BF and MAT in bone, and 2) develop pharmacological tools to modify this process. In Aim 1, mouse genetic approaches will be used to conditionally delete Pkd1 and TAZ in osteoblasts and define the functional interdependence of Pkd1 and TAZ in regulating bone mass. In Aim 2, lineage tracing studies will determine the respective roles OAT or altered lineage commitment in the reciprocal regulation of Ob-BF and MAT in these mice. In Aim 3, we will pursue pre-therapeutic lead design and optimization of novel small molecules that “staple” the C-terminal regions of Pkd1 and Pkd2, and stimulate Pkd1/Pkd2/TAZ to promote osteoblastogenesis and inhibit adipogenesis in Ob cultures. Establishing that Pkd1/Pkd2/TAZ regulates OAT in vivo would be a paradigm shift that challenges prevailing concepts of how bone mass is maintained in health and disease. Optimizing lead analogues that activate this complex would potentially provide a novel treatment for OP. In Aim 4, which will be undertaken in the R33 phase only if the expected outcomes of Aims 1-3 are achieved, we will synthesize sufficient quantities of the lead compounds to characterize in vivo pharmacokinetic (PK) properties and safety profiles, and test the ability of the most promising compounds to prevent bone loss in preclinical mouse models of OP. A role of the mechanosensing complex Pkd1/Pkd2/TAZ to regulate Ob to adipocyte conversion provides a new perspective for understanding the pathological significance of the reciprocal relationship between bone formation and MAT in OP and defines a new therapeutic target for developing drugs to treat OP that uniquely stimulate Ob-mediated bone formation and inhibit MAT through activation of Pkd1/Pkd2/TAZ in mature osteoblasts.

成骨细胞（OBS）与间充质干细胞（MSC）区分开，并在骨表面极化以产生填充破骨细胞介导的骨骼分辨率产生的空腔的新骨。 Polycystins 1和2（PKD1/PKD2） TAZ在成熟的OBS中形成了一种机械化合物，该复合物在骨骼的维持中起着重要作用大量的。小鼠成熟观察中PKD1/TAZ的遗传丧失导致骨质减少症，由OB介导的降低引起骨形成（OB-BF）和骨髓脂肪（MAT）的意外增加。这种反关系在化合物PKD1/TAZ缺陷小鼠中的OB-BF和骨髓脂肪细胞之间类似于某些形式人骨质疏松症（OP）。 OP中的MAT增加被认为是由于MSC分化向脂肪细胞以OBS为代价，脂肪细胞释放旁分泌因子据称抑制了OB- bf。但是，由于成熟OB中PKD1/TAZ的破坏而导致的MAT增加不容易解释对血统承诺的影响。相反，PKD1/TAZ在OBS中的直接影响增加了其他可能性机制负责将OBS转化为脂肪细胞。意外的可能性是脂肪细胞出现来自obs的转变。我们提出了一种新的假设，即骨骼中的物理力微环境通过激活PKD1/PKD2/TAZ来调节对脂肪细胞（OAT）的OB转变。 R61阶段将：1）探索PKD1/PKD2/TAZ在OBS中反向调节OB-BF和骨骼中的垫子，以及2）开发用于修改此过程的药物工具。在AIM 1中，小鼠遗传方法将用于有条件地删除成骨细胞中的PKD1和TAZ，并定义 PKD1和TAZ在调节骨骼中。在AIM 2中，谱系追踪研究将确定燕麦的相对作用或在这些小鼠的OB-BF和MAT的相互调节中改变谱系承诺。在AIM 3中，我们将追求“固定” C末端区域的新型小分子的治疗前铅设计和优化 PKD1和PKD2，并刺激PKD1/PKD2/TAZ促进成骨细胞生成并抑制OB中的脂肪形成文化。确定pkd1/pkd2/taz在体内调节燕麦将是一个范式转变，挑战骨质如何在健康和疾病中保持骨骼的概念。优化铅类似物激活该复合物可能会为OP提供新的治疗方法。在AIM 4中将进行 R33阶段仅在实现目标1-3的预期结果时，我们将合成足够的数量铅化合物的表征体内药代动力学（PK）特性和安全剖面，并测试在OP的临床前小鼠模型中，最有希望的化合物的作用是防止骨质流失的作用。机械感应复合物pkd1/pkd2/taz调节OB到脂肪细胞转换提供了新的视角理解骨形成与MAT之间相互关系的病理意义在OP中定义了一种新的治疗靶标，用于开发药物来治疗OP，以刺激OB介导的OP 骨形成并通过成熟成骨细胞中的PKD1/PKD2/TAZ的激活来抑制MAT。