The Role of Primary Neuronal Cilia in Appetite and Satiation

初级神经元纤毛在食欲和饱腹感中的作用

• 批准号: 7913944
• 负责人: Nicolas F Berbari
• 金额: $ 5.05万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7913944
• 关键词: Adult; Alleles; Anosmia; Attenuated; Cilia; Clinical; Cystic Kidney Diseases; Data; Defect; Desire for food; Development; Developmental Process; Disease; Embryo; Embryonic Development; Feeding behaviors; Genes; Goals; Hair; Health; Heart Diseases; Hereditary Disease; Homeostasis; Human Genetics; Hyperphagia; Hypertension; Hypothalamic structure; In Vitro; Lead; Left; Limb structure; Molecular; Mus; Nervous System Physiology; Neural tube; Neuraxis; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nutrition Disorders; Obesity; Organelles; Pathway interactions; Pattern; Play; Principal Investigator; Publishing; Regulation; Research; Retinal Diseases; Role; Satiation; Sensory; Signal Transduction; Societies; Stroke; System; Therapeutic; Tissues; United States; cell type; embryo tissue; energy balance; experience; high risk; insight; mature animal; mouse model; mutant; novel; programs; public health relevance; therapeutic target; transmission process

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.

描述（由申请人提供）：近年来，对以前被忽视的细胞器，初级纤毛的功能的研究经历了一个繁荣。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，并且是左右身体轴的规格以及神经管和肢体图案所必需的。此外，人类遗传性疾病，称为纤毛病，具有广泛的临床特征，如囊性肾病、视网膜病、嗅觉丧失和肥胖症。虽然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，但纤毛在成年哺乳动物系统中的组织稳态中的功能仍然很大程度上未被探索。我们对纤毛在成年人中的功能的理解存在差距，这是由于在纤毛无效突变体中观察到的早期胚胎致死性。为了克服这一局限性，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，在成年动物中诱导纤毛损失。使用这种方法，Yoder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。最近发表的数据表明，成年小鼠，更具体地说是下丘脑中纤毛的损失，会导致由于摄食过多引起的肥胖。因此，我的中心假设是，在中枢神经系统（CNS）的神经元上的初级纤毛作为一个感觉细胞器参与接收，传输，或饱腹感信号的调节。本申请的主要目标是阐明初级纤毛与调节进食行为和饱腹信号的途径之间的联系。为了实现这一目标，我建议：（1）确定特定的信号（S）丢失，获得，或改变纤毛小鼠模型，导致食欲过盛和肥胖，（2）和分析在体外神经元纤毛是如何用于接收和/或传输这些特定的促食欲或促食欲的信号。这些研究目标不仅将为CNS中纤毛如何维持适当的能量平衡和稳态提供新的见解，还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潜在的治疗目标提供新的机会，这些目标旨在减轻美国最普遍和最昂贵的健康问题之一。 公共卫生关系：肥胖是发达社会中最常见的营养失调之一，并且与许多重大健康问题相关，包括II型糖尿病、高血压、中风和心脏病的较高风险。最近，人们发现在身体的大多数细胞类型上发现的被称为纤毛的小的毛发状细胞器参与调节进食行为，纤毛的缺陷通过未知的机制导致肥胖。该项目的目标是揭示纤毛缺陷如何改变进食行为，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的潜在疗法。