Nkx3.2 nuclear localization and cartlidge formation

描述(由申请人提供)： 关节炎是一种广泛存在的使人衰弱的疾病，关节软骨会瓦解。体外再生软骨可能是治疗这些疾病的可行方法的一部分。要了解软骨是如何降解的，以及如何通过生物工程产生新的软骨，需要彻底了解软骨形成过程中发生的信号事件。我们的长期目标是揭示胚胎中软骨形成的机制，这将为治疗关节炎和其他骨骼疾病提供知识。本研究的目的是探讨Nkx3.2在软骨形成过程中的表达调控和核定位。我们的中心假设是Nkx3.2的调控是软骨分化的关键机制。我们将通过以下具体目标来验证我们的假设：1.研究Nkx3.2核定位受促软骨信号Shh、BMP和Sox9控制的机制。2.检测软骨抑制信号TNF-α和IL-1(I)对Nkx3.2表达和核定位的影响。3.确定Nkx3.2是否促进人骨髓间充质干细胞向软骨分化。Nkx3.2是一种重要的蛋白质，因为它不仅促进软骨形成，而且还能防止软骨细胞肥大。因此，Nkx3.2是一个可能被导入祖细胞以促进永久软骨形成的候选基因。了解这种蛋白的调控将有助于我们未来的研究，在成人干细胞中引入Nkx3.2，以指导和保持软骨生物工程中的分化软骨细胞表型，并开发治疗关节炎的药物。

DESCRIPTION (provided by applicant): Arthritis is a widespread debilitating disease in which the joint cartilage becomes disintegrated. Regenerating cartilage in vitro may be part of a plausible treatment for these conditions. The understanding how cartilage is degraded and how to produce new cartilage through bioengineering requires a thorough understanding of the signaling events that take place during cartilage formation. Our long-range goal is to unveil the mechanisms that govern cartilage formation in the embryo, which will provide the knowledge for treating arthritis and other skeletal diseases. The objective of this proposal is to investigate the regulation of Nkx3.2 expression and nuclear localization during chondrogenesis. Our central hypothesis is that the control of Nkx3.2 is a key mechanism to cartilage differentiation. We will test our hypothesis by pursuing the following Specific Aims: 1. Investigate the mechanisms of Nkx3.2 nuclear localization controlled by pro-chondrogenic signals Shh, BMP and Sox9. 2. Examine the effect of cartilage-inhibiting signals TNF-a and IL-1 (i on Nkx3.2 expression and nuclear localization. 3. Determine if Nkx3.2 promotes cartilage differentiation in human mesenchymal stem cells. Nkx3.2 is an important protein because it not only promotes cartilage formation, but also prevents chondrocyte hypertrophy. Thus, Nkx3.2 is a plausible candidate to be introduced into the progenitor cells in order to promote the formation of permanent cartilage. Understanding the regulation of this protein will help us in our future research of introducing Nkx3.2 in adult stem cells to direct and maintain differentiated chondrocyte phenotype in our endeavor of cartilage bioengineering, and on developing remedies for arthritis.