Tissue-specific regulation of ciliary function by the transition zone

描述（由申请人提供）：人体中的许多细胞从其表面具有称为初级纤毛的单一突起。虽然初级纤毛的存在已被确认超过一个世纪，直到最近才变得清楚，他们的功能在检测和解释重要的细胞间的线索。其中一些线索，如刺猬信号，是胚胎模式和成人组织稳态的关键调节因子。因此，Hedgehog信号的缺陷可能导致出生缺陷和某些形式的癌症。类似地，初级纤毛的缺陷可引起罕见的先天性综合征，如Meckel和Joubert综合征，可能是更常见的人类疾病如多囊肾病的基础，并且对某些癌症的进展很重要。 纤毛缺陷的哺乳动物细胞不能对Hedgehog信号做出反应。我们已经发现，一些组织在发育的特定时期具有纤毛，在成体组织中，一些细胞可以具有纤毛，而另一些则没有。我们假设，控制哪些细胞是纤毛形状组织如何响应纤毛解释信号。我们最近发现了一类新的基因，称为构造基因，它支持某些组织中的纤毛发生，并控制其他组织中的纤毛膜组成。构造与纤毛疾病蛋白相互作用并共定位在纤毛的一个亚结构域，称为过渡区。我们建议研究构造和它们的相互作用，以了解组织特异性调节纤毛功能。具体来说，我们将回答三个互补的问题：1）不同的构造调节纤毛在不同的组织？ 2)构造和其他过渡区成分是否通过调节蛋白质向纤毛的转运而促进纤毛发生？ 3)构造基因是否与人类疾病基因（如梅克尔综合征和多囊肾病的潜在基因）一起发挥作用，以调节纤毛发生？ 拟议中的实验将联合收割机遗传学、成像和生物化学方法结合起来，为这些问题提供答案。这项工作将阐明构造和相关蛋白质有助于纤毛功能的机制，为纤毛在发育中的功能以及它们在人类纤毛病中的功能障碍提供分子和细胞生物学见解。 公共卫生相关性：初级纤毛是在许多人类细胞上发现的小突起，参与接收和解释来自其他细胞的信号。这些纤毛信号传导事件的中断有助于出生缺陷、癌症、多囊肾病和其他人类疾病。我们建议研究控制纤毛形成和蛋白质组成的机制，以提供对纤毛相关疾病的分子理解。

DESCRIPTION (provided by applicant): Many cells in the human body possess a singular projection from their surface called a primary cilium. Although the existence of primary cilia has been recognized for over a century, only recently has it become clear that they function in the detection and interpretation of important intercellular cues. Some of these cues, such as Hedgehog signals, are key regulators of embryonic patterning and adult tissue homeostasis. Consequently, defects in Hedgehog signaling can cause birth defects and some forms of cancer. Similarly, defects in primary cilia can cause rare congenital syndromes such as Meckel and Joubert syndromes, may underlie more common human diseases such as polycystic kidney disease, and are important for the progression of some cancers. Mammalian cells with ciliary defects fail to respond to Hedgehog signals. We have found that some tissues are ciliated at specific times in development, and within adult tissues, some cells can be ciliated and others not. We hypothesize that the control of which cells are ciliated shapes how tissues respond to cilium-interpreted signals. We have recently identified a class of novel genes called the Tectonics, which support ciliogenesis in some tissues and control ciliary membrane composition in others. The Tectonics interact and co-localize with ciliary disease proteins at a subdomain of the cilium called the transition zone. We propose to study Tectonics and their interactors to understand the tissue-specific regulation of ciliary functions. Specifically, we will answer three complementary questions: 1) Do different Tectonics regulate ciliogenesis in different tissues? 2) Do Tectonics and other transition zone components promote ciliogenesis by regulating protein transport to the cilium? 3) Do Tectonics function with human disease genes, such as those underlying Meckel syndrome and polycystic kidney disease, to regulate ciliogenesis? The proposed experiments combine genetic, imaging and biochemical approaches to provide answers to these questions. This work will elucidate the mechanism by which Tectonics and associated proteins contribute to ciliary function, providing molecular and cell biological insights into how cilia function in development and how they misfunction in human ciliopathies. PUBLIC HEALTH RELEVANCE: Primary cilia are small projections found on many human cells involved in receiving and interpreting signals from other cells. Disruption of these ciliary signaling events contributes to birth defects, cancer, polycystic kidney disease, and other human disorders. We propose to investigate the mechanisms controlling cilium formation and protein composition to provide a molecular understanding of cilia-related diseases.)