The Role of Primary Neuronal Cilia in Appetite and Satiation

描述（由申请人提供）：近年来，对一种以前被忽视的细胞器——初级纤毛的功能的研究出现了蓬勃发展。纤毛曾经被认为是退化的，现在人们知道它在许多发育过程和疾病中起着至关重要的作用。例如，初级纤毛在早期胚胎发育中是必不可少的，它是确定左右身体轴以及神经管和肢体图案的必要条件。此外，被称为纤毛病的人类遗传性疾病具有广泛的临床特征，如囊性肾病、视网膜病变、嗅觉缺失和肥胖。虽然对纤毛在胚胎组织和发育过程中的功能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，纤毛在组织稳态中的功能仍未得到充分研究。我们对成人纤毛功能的理解的差距是由于在纤毛无突变体中观察到的早期胚胎致命性。为了克服这一限制，我正在利用纤毛形成所需基因的条件等位基因，这允许在纤毛在胚胎发育中完成其作用后，在成年动物中诱导纤毛丢失。利用这种方法，Yoder实验室先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，成年小鼠纤毛的缺失，尤其是下丘脑纤毛的缺失，会导致贪食导致肥胖。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一种感觉细胞器参与接收、传递或调节饱腹感信号。本应用的主要目的是阐明初级纤毛与调节摄食行为和饱腹感信号的途径之间的联系。为了实现这一目标，我建议：(1)确定纤毛小鼠模型中导致贪食和肥胖的特定信号丢失、获得或改变，(2)并在体外分析神经元纤毛如何用于接收和/或传输这些特定的厌氧或厌氧信号。这些研究目标不仅将为CNS纤毛如何维持适当的能量平衡和稳态提供新的见解，而且还将为其他神经元上的纤毛如何被利用提供新的见解。此外，了解肥胖小鼠模型背后的分子机制将为潜在的治疗靶点提供新的机会，以减轻美国最普遍和最昂贵的健康问题之一。

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.