The Role of Primary Neuronal Cilia in Appetite and Satiation

描述(由申请人提供)：近年来，对一个以前被忽视的细胞器--初级纤毛的功能的研究经历了蓬勃发展。纤毛曾经被认为是退化的，现在已知在许多发育过程和疾病中发挥着关键作用。例如，初级纤毛在早期胚胎发育中是必不可少的，是确定左右体轴以及神经管和肢体模式所必需的。此外，人类遗传性疾病，称为纤毛疾病，具有广泛的临床特征，如囊性肾病、视网膜病变、嗅觉障碍和肥胖。虽然对胚胎组织和发育过程中纤毛功能的分析已经揭示了它们作为信号中心的作用，但在成年哺乳动物系统中，纤毛在组织动态平衡中的功能仍然很大程度上尚不清楚。我们对成人纤毛功能的理解上的这种差距是由于在纤毛缺失突变体中观察到的早期胚胎致死。为了克服这一局限，我正在利用纤毛形成所需基因的条件等位基因，这允许在纤毛完成其在胚胎发育中的作用后，诱导成年动物失去纤毛。使用这种方法，约德实验室以前已经证明了初级纤毛在调节摄食行为中的重要作用。最近公布的数据显示，成年小鼠失去纤毛，更具体地说，是下丘脑，由于吞噬过度而导致肥胖。因此，我的中心假设是，中枢神经系统(CNS)神经元上的初级纤毛作为感觉器参与接收、传输或调节饱腹感信号。这一应用的主要目的是阐明初级纤毛与调节取食行为和饱腹感信号的通路(S)之间的联系。为了实现这一目标，我建议：(1)确定纤毛小鼠模型中导致过度吞噬和肥胖的特定信号(S)的丢失、获得或改变，(2)并在体外分析神经元纤毛如何用于接收和/或传递这些特定的厌氧或厌氧信号。这些研究目标不仅将为CNS中的纤毛如何维持适当的能量平衡和动态平衡提供新的见解，也将为其他神经元上的纤毛如何被利用提供见解。此外，了解这种小鼠模型中肥胖背后的分子机制将为针对减轻美国最普遍和最昂贵的健康问题之一的潜在治疗目标提供新的机会。 公共卫生相关性：肥胖是发达国家最常见的营养失调之一，与许多重大健康问题有关，包括II型糖尿病、高血压、中风和心脏病的风险较高。最近发现，在人体大多数细胞类型上发现的小毛状细胞器纤毛参与调节摄食行为，纤毛缺陷通过未知的机制导致肥胖。这个项目的目标是揭示纤毛缺陷是如何改变摄食行为的，因为更好地了解饱腹感和食欲背后的机制将有助于开发治疗肥胖症的潜在疗法。

DESCRIPTION (provided by applicant): In recent years, research on the functions of a previously overlooked organelle, the primary cilium, has experienced a boom. Once thought to be vestigial, the cilium is now known to play crucial roles in a number of developmental processes and diseases. For example, primary cilia are essential in early embryonic development and are required for specification of the left-right body axis as well as for neural tube and limb patterning. Furthermore, human genetic disorders, termed ciliopathies, present with a broad range of clinical features such as cystic kidney disease, retinopathy, anosmia, and obesity. While the analysis of cilia function in embryonic tissues and through development has revealed much about their roles as signaling centers, the functions of cilia in tissue homeostasis in adult mammalian systems remain largely unexplored. This gap in our understanding of cilia function in adults is due to the early embryonic lethality observed in cilia null mutants. In order to overcome this limitation, I am utilizing conditional alleles of genes required for cilia formation, which allows for induced cilia loss in the adult animal after the cilia have fulfilled their roles in embryonic development. Using this approach, the Yoder lab has previously demonstrated an important role for the primary cilium in regulating feeding behavior. Recently published data show that loss of cilia in the adult mouse, and more specifically in the hypothalamus, results in obesity due to hyperphagia. Thus, my central hypothesis is that the primary cilium on neurons in the central nervous system (CNS) act as a sensory organelle involved in reception, transmission, or regulation of satiety signaling. The major objective of this application is to elucidate the connection between the primary cilium and the pathway(s) regulating feeding behavior and satiety signals. To accomplish this objective, I propose: (1) to determine the specific signal(s) lost, gained, or altered in the cilia mouse model that result in hyperphagia and obesity, (2) and to analyze in vitro how neuronal cilia are utilized for the reception and/or transmission of these specific anorexigenic or orexigenic signals. These research goals will not only provide novel insights into how cilia in the CNS function to maintain proper energy balance and homeostasis but will also provide insights as to how cilia on other neurons are utilized. Furthermore, understanding the molecular mechanisms behind the obesity in this mouse model will provide new opportunities for potential therapeutic targets directed at attenuating one of the most pervasive and costly health issues in the United States. PUBLIC HEALTH RELEVANCE: Obesity is one of the most common nutritional disorders in developed societies and is associated with a number of significant health issues including higher risks of type II diabetes mellitus, hypertension, stroke, and heart disease. Recently it has been found that small hair-like organelles found on most cell types of the body called cilia are involved in regulating feeding behavior and defects in cilia lead to obesity through unknown mechanisms. The goal of this project is to uncover how cilia defects alter feeding behavior because a better understanding of the mechanisms behind satiety and appetite will allow for the development of potential therapeutics to treat obesity.