The Role of Basa Bodies in Wnt Signaling

描述(由申请人提供)： 纤毛疾病是一组重叠的临床疾病，由初级纤毛及其锚定结构，即基底体的缺陷引起。这一群体虽然个别罕见，但对人口遗传病负担有很大贡献。部分受到基因发现的推动，初级纤毛现在被认为是旁分泌信号调节的中心组成部分，影响了我们对许多发育过程和疾病机制的理解。在之前的资助期间，我们确定了基础小体蛋白在调节规范和非规范Wnt信号方面的作用。利用这些信息，我们继续开发检测方法来探索这些观察的机制基础，并研究在睫毛疾病患者中发现的突变的影响。我们最近的研究也揭示了一个重要的，以前没有被认识到的，基本身体蛋白的作用。我们发现，一些基底体蛋白调节蛋白酶体介导的信号成分的选择性降解，从而在不同的信号转导级联中发挥动态平衡调节作用。在这次更新中，我们提出了三个目标。首先，我们将检验这一假设，即所观察到的蛋白酶体缺陷至少部分是由蛋白酶体调节成分的缺陷组成所驱动的，并询问这些缺陷是配体依赖的还是独立的。其次，基于蛋白酶体功能障碍导致纤毛病变信号表型的假设，我们将询问纤毛蛋白质组中发现的蛋白酶体亚基突变是否可以导致不同纤毛表型的患者的因果等位基因或修饰等位基因。最后，我们的初步数据表明，蛋白酶体的化学激动剂可以改善细胞和活斑马鱼胚胎中的信号表型，增加了它们可能具有治疗益处的可能性。因此，我们将研究这些激动剂减轻或改善纤毛病变表型的能力。 老鼠模型。综上所述，我们的研究将揭示纤毛疾病的基本机制，潜在地提供了这种细胞器功能的正交视图， 并将提供潜在的见解，为人体临床试验奠定基础。

DESCRIPTION (provided by applicant): The ciliopathies are a group of >100 overlapping clinical disorders caused by defects in the primary cilium and its anchoring structure, the basal body. Although individually rare, this group contributes significantly to the population genetic disease burden. Fueled in part by genetic discoveries, the primary cilium is now appreciated to be a central component of paracrine signaling regulation, influencing our understanding of numerous developmental processes and disease mechanisms. During the previous funded period, we established the role of basal body proteins in regulating aspects of both canonical and non-canonical Wnt signaling. Using this information, we went on develop assays to probe the mechanistic basis of these observations and to study the effect of mutations found in ciliopathy patients. Our recent studies have also revealed a major, previously unappreciated, role of basal body proteins. We discovered that some basal body proteins regulate the selective proteasome-mediated degradation of signaling components and thus act as a homeostatic regulator of diverse signal transduction cascades. In this renewal, we propose three Aims. First, we will test the hypothesis that the observed proteasomal defects are driven, at least in part, by defective composition of the regulatory components of the proteasome and ask whether such defects are ligand-dependent or independent. Second, based on the hypothesis that proteasomal dysfunction contributes to the signaling phenotypes pathognomonic of ciliopathies, we will ask whether mutations in the 64 proteasomal subunits found in the ciliary proteome can contribute causal or modifying alleles to patients with diverse ciliopathy phenotypes. Finally, our preliminary data have indicated that chemical agonists of the proteasome can ameliorate signaling phenotypes in both cells and live zebrafish embryos, raising the possibility that they might have therapeutic benefit. Therefore, we will investigate the ability of such agonists to attenuate or ameliorate ciliopathy phenotypes in a mouse model. Taken together, our studies will inform the fundamental mechanisms that underpin ciliopathies, potentially providing an orthogonal view of the functions of this organelle, and will provide potential insights that can lay the foundation for clinical trials in humans.