ROLE OF OSTEOCYTE TbetaRII IN PERILACUNAR REMODELING AND BONE METASTASES

项目摘要/摘要 骨骼是一个动态的、反应灵敏的组织，所有其他器官都用它来保持稳定和结构。 为了保持骨骼的完整性，骨细胞不断地参与有组织的破坏 以及骨基质的重建，这一过程被称为骨重建。虽然很多人都知道 成骨细胞和降解破骨细胞的活性，具有 骨细胞被证明是骨重建的中心调节器，但收到的信息较少 对价。骨细胞存在于骨基质中，是骨骼中最丰富的细胞， 并通过复杂的小管突起网络相连，这些小管突起遍布 骨头。这个网络允许骨细胞对机械刺激，如负载或化学物质做出反应 刺激物，如生长因子。作为对这些刺激的反应，骨细胞重塑其邻近的基质 这一过程被称为楔周重塑(PLR)。转化生长因子-β(转化生长因子β)是 研究最多的是骨骼中的生长因子，已被证明调节许多过程。 通过II型转化生长因子β受体(T-βRII)向骨细胞传递信号。然而，它的确切功能是 TβRII在成骨细胞驱动的PLR中的作用仍不清楚。此外，当骨基质在过程中暴露时 重塑，储存活性-转化生长因子β被释放，因此局部集中这种强有力的生长 因素增加。暴露的基质，结合蛋白和生长因子随时可用，具有 事实证明，它是癌症转移和发展的诱人场所。这导致了 释放更多的生长因子，并在骨骼退化、肿瘤发展、 最终增加了骨折和发病率。因此，这个项目检验了这样一个假设 TβRII依赖的信号转导调控PLR，进而通过骨细胞调控骨转移 通过转化生长因子β依赖途径的进展。一项为期三年的重点调查被提议 确定转化生长因子β调控健康人骨细胞活性的细胞和分子机制 在前列腺癌的情况下，骨转移。在第一个目标中，我将生产一只老鼠 建立具有骨细胞特异性TβRII基因敲除的模型，并确定其对预后的影响 PLR.在第二个目的中，我将评估接种小鼠模型后的骨肿瘤负担 前列腺癌细胞。这种方法将提供关于转化生长因子β信号如何控制PLR的深入了解 并找出控制癌症骨转移恶性循环的新机制。

PROJECT SUMMARY/ABSTRACT The skeleton is a dynamic and responsive tissue that all other organs use for stability and structure. To maintain the integrity of skeleton, bone cells are constantly involved in the organized destruction and rebuilding of the bone matrix, a process known as bone remodeling. While much is known about the activity of the bone forming osteoblasts and the bone degrading osteoclasts, the cell that has been shown to be the central regulator of bone remodeling, the osteocyte, has received less consideration. Osteocytes reside inside the bone matrix, are the most abundant cell in the skeleton, and are connected through an intricate network of canalicular processes stretching throughout the bone. This network allows osteocytes to respond to mechanical stimuli such as load, or chemical stimuli such as growth factors. In response to these stimuli, osteocytes remodel their adjacent matrix in a process known as perilacunar remodeling (PLR). Transforming growth factor-beta (TGFβ), one of the most prominently studied growth factors in bone, has been shown to regulate many processes in bone cells by signaling through the type-II TGFβ receptor (TβRII). However, the exact function of TβRII in osteocyte driven PLR remains unknown. Furthermore, when bone matrix is exposed during remodeling, stored active-TGFβ is liberated and therefore the local concentration of this potent growth factor increased. The exposed matrix, with binding proteins and growth factors readily available, has proven to be an attractive site for cancer to metastasize and develop tumors. This leads to the release of more growth factor and repeats in a vicious cycle of bone degradation, tumor development, and ultimately increased fracture and morbidity. Therefore, this project tests the hypothesis that TβRII dependent signaling controls PLR, and further, that osteocytes regulate bone metastasis progression through a TGFβ dependent pathway. A focused, three-year investigation is proposed to determine the cellular and molecular mechanisms behind TGFβ control of osteocyte activity in healthy bone and in the case of prostate cancer bone metastasis. In the first Aim, I will produce a mouse model with an osteocyte specific knockout of TβRII and determine the effect this has on outcomes of PLR. In the second Aim, I will assess the bone tumor burden after inoculation of the mouse model with prostate cancer cells. This approach will provide insight into how TGFβ signaling controls PLR and identify new mechanisms controlling the vicious cycle of cancer bone metastasis.