The Role of Basa Bodies in Wnt Signaling

描述（由申请人提供）： 纤毛病是由初级纤毛及其锚定结构（基体）的缺陷引起的一组>100种重叠的临床病症。虽然个体罕见，但这一群体对人口遗传疾病负担有重大贡献。在遗传学发现的推动下，初级纤毛现在被认为是旁分泌信号调节的核心组成部分，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，我们建立了基体蛋白在规范和非规范Wnt信号传导方面的作用。利用这些信息，我们继续开发检测方法来探索这些观察结果的机制基础，并研究在纤毛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主要的，以前不受重视的，基体蛋白的作用。我们发现，一些基体蛋白调节选择性蛋白酶体介导的降解信号成分，从而作为一个稳态调节器的不同信号转导级联。在这次更新中，我们提出了三个目标。首先，我们将测试的假设，所观察到的蛋白酶体的缺陷驱动，至少部分地，由蛋白酶体的监管组件的缺陷组合物，并询问这种缺陷是配体依赖性或独立的。其次，基于蛋白酶体功能障碍导致纤毛病变的信号表型特异性的假设，我们将询问在纤毛蛋白质组中发现的64个蛋白酶体亚基中的突变是否可以为具有不同纤毛病变表型的患者贡献因果或修饰等位基因。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，提高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在一个受试者中减弱或改善纤毛病变表型的能力。 小鼠模型综上所述，我们的研究将为纤毛病变的基本机制提供信息，可能提供这种细胞器功能的正交视图， 并将提供潜在的见解，为人类临床试验奠定基础。

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.