CDC 42 BIM AND THE OSTEOCLAST

CDC 42 BIM 和破骨细胞

• 批准号: 7729102
• 负责人: Steven L Teitelbaum
• 金额: $ 38万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-18 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7729102
• 关键词: Address; Animals; Apoptosis; Arthritis; Bone Resorption; Cell Count; Cell Proliferation; Cell physiology; Cells; Cytoskeleton; Death Rate; Disease; Equilibrium; Guanosine Triphosphate Phosphohydrolases; Longevity; Modeling; Monomeric GTP-Binding Proteins; Mus; Osteoblasts; Osteoclasts; Osteoporosis; Positioning Attribute; Postmenopausal Osteoporosis; Process; Protein Isoforms; Proteins; Role; Series; Structure; Tissues; base; bone; bone loss; bone mass; cdc42 GTP-Binding Protein; cell type; in vivo; member; novel; pro-apoptotic protein; research study; rho; rho GTP-Binding Proteins; selective expression; therapeutic target

Various members of the Ras superfamily of small GTPases, which comprise over 200 proteins, are expressed selectively in all cells, where they perform a range of cellular functions. A well-studied subfamily is that of the Rho GTPases, with the three best-understood members being Rho, Rac and cdc42. These molecules, including three isoforms of Rac, a number of Rho proteins and cdc42, a single gene product, regulate cell proliferation, differentiation, survival and many aspects of the cytoskeleton. We find cdc42 a particularly important regulator of osteoclast (OC) number and function. While increased cdc42 activity causes osteoporosis in mice, animals lacking the active GTPase specifically in their OCs have enhanced bone mass. Thus, cdc42 is a candidate therapeutic target for states of accelerated bone resorption. cdc42 deletion in OCs enhances their number by suppressing apoptosis, a process accompanied by increased amounts of the proapoptotic protein Bim. However, the impact of osteoclastic Bim on cell number and resorptive capacity in the context of cdc42 presence or absence is unknown. Moreover, Bim is also expressed in osteoblasts (OBs), where it regulates their lifespan and function. Finally, while Bim structure/function studies have been performed in a number of cell types, the residues that control OC and OB apoptosis are unknown. Based on these facts we hypothesize that: 1) absence of cdc42 in OCs arrests pathological bone loss; 2) cdc42 and Bim act in concert in OCs to regulate apoptosis of bone resorptive cells, while Bim controls the OB and 3) specific residues in Bim govern its capacity to regulate OC and OB apoptosis. Given that we have generated mice with gain or loss of cdc42 function in OCs and have the capacity to selectively delete Bim in OCs or OBs in vivo, we are positioned to address the following specific aims: 1) determine the role of osteoclastic cdc42 in pathological bone loss, 2) determine how cdc42 and Bim, expressed in OCs and OBs, regulate apoptosis and bone mass in resorptive cells and 3) identify the specific residues in Bim that govern its capacity to regulate OC and OB apoptosis.

小GTP酶的Ras超家族的各种成员，其包含超过200种蛋白质，在所有细胞中选择性地表达，其中它们执行一系列细胞功能。Rho GTP酶是一个研究得很好的亚家族，其中三个最好理解的成员是Rho，Rac和cdc 42。这些分子，包括Rac的三种亚型，许多Rho蛋白和cdc 42，一个单一的基因产物，调节细胞增殖，分化，存活和细胞骨架的许多方面。我们发现cdc 42是破骨细胞（OC）数量和功能的一个特别重要的调节因子。虽然cdc 42活性增加导致 在小鼠骨质疏松症中，特别是在其OC中缺乏活性GT3的动物具有增强的骨量。因此，cdc 42是加速骨吸收状态的候选治疗靶点。在OC中cdc 42缺失通过抑制细胞凋亡增加了它们的数量，这一过程伴随着促细胞凋亡蛋白Bim的量增加。然而，在cdc 42存在或不存在的情况下，骨细胞Bim对细胞数量和吸收能力的影响尚不清楚。此外，Bim还在成骨细胞（OB）中表达， 调节它们的寿命和功能最后，虽然Bim结构/功能的研究已经在许多细胞类型中进行，控制OC和OB凋亡的残基是未知的。基于这些事实，我们假设：1）OC中cdc 42的缺失阻止了病理性骨丢失; 2）cdc 42和Bim在OC中协同作用以调节骨吸收细胞的凋亡，而Bim控制OB; 3）Bim中的特定残基控制其调节OC和OB凋亡的能力。鉴于我们已经产生了在OC中具有cdc 42功能获得或丧失的小鼠，并且具有在体内选择性地删除OC或OB中的Bim的能力，我们定位于解决以下具体目标：1）确定骨细胞cdc 42在病理性骨丢失中的作用，2）确定cdc 42和Bim如何在OC和OB中表达，调节再吸收细胞中的凋亡和骨量; 3）鉴定Bim中控制其调节OC和OB凋亡的能力的特定残基。