Genetic Dissection ot the Central GLP-1 System

描述（由申请人提供）：人们对安全有效地降低糖尿病患者血糖的新疗法仍有浓厚的兴趣。天然存在的调节肽胰高血糖素样肽1 （GLP-1）显示出多种潜在的抗糖尿病药物的理想作用，蛋白酶抗性长效GLP-1类似物目前可用于治疗2型糖尿病。GLP-1也是一种内源性神经肽，在中枢神经系统（CNS）中发挥作用，但鲜为人知。鉴于一种或多种GLP-1类似物用于治疗糖尿病患者的可能性越来越大，了解GLP-1的核心作用与预测持续GLP-1给药的生物学后果越来越相关。GLP-1在中枢神经系统的表达主要是在尾侧孤立束核（NTS）内的一个细胞亚群中。尾侧NTS亚核接收并处理来自胸腔和腹腔脏器的内脏感觉信息，NTS与各种大脑区域相互连接，包括下丘脑区域，如调节食欲功能的弓状核。此外，NTS位于心室周围器官后区（AP）附近，并含有开孔毛细血管，可能允许循环肽进入核。因此，NTS（包括GLP-1细胞）在处理来自各种神经和体液来源的信息方面处于有利地位。了解哪些肽参与能量平衡，调节脑干GLP-1神经元的神经元活动将有助于理解中枢GLP-1调控。我们提出了一个预测模型：1)NTS中的GLP-1神经元共同表达瘦素受体（Ob-R），并且瘦素管理诱导这些神经元中SOCS-3和STAT-3的激活；2)瘦素诱导GLP-1 NTS神经元中的膜去极化和/或增加兴奋性突触活性；3)GLP-1神经元中特异性瘦素受体的缺失将导致嗜食和肥胖。本应用程序中提供的研究旨在直接测试该模型的不同组成部分。

DESCRIPTION (provided by applicant): There remains intense interest in new therapies that safely and effectively lower blood glucose in diabetic subjects. The naturally occurring regulatory peptide glucagon-like peptide 1 (GLP-1) exhibits multiple desirable actions for a potential anti-diabetic agent, and protease-resistant long-acting GLP-1 analogs are currently available for the treatment of Type 2 diabetes. GLP-1 is also an endogenous neuropeptide that exerts actions in the central nervous system (CNS) that are less well understood. Given the increasing likelihood that one or more GLP-1 analogues will be used to treat diabetic patients, understanding the central role of GLP-1 is increasingly relevant for predicting the biological consequences of sustained GLP-1 administration. The CNS expression of GLP-1 is primarily in a subpopulation of cells within the caudal nucleus tractus solitaries (NTS). Caudal NTS subnuclei receive and process viscerosensory information from thoracic and abdominal viscera and the NTS is reciprocally connected with various brain areas, including hypothalamic areas such as the arcuate that regulate appetitive functions. Additionally, the NTS is located adjacent to a circumventricular organ, the area postrema (AP), and contains fenestrated capillaries, potentially allowing circulating peptides access to the nucleus. The NTS (including GLP-1 cells) is therefore in a prime position to process information arising from a variety of neural and humoral sources. Understanding which peptides, involved in energy balance, modulate neuronal activity of brainstem GLP-1 neurons will aid in the understanding of central GLP-1 regulation. We propose a model that predicts: 1) GLP-1 neurons in the NTS co-express the leptin receptor (Ob-R), and that leptin administration induces the activation of SOCS-3 and STAT-3 in these neurons, 2) leptin induces a membrane depolarization and/or increases excitatory synaptic activity within GLP-1 NTS neurons, and 3) deletion of leptin receptors specifically in GLP-1 neurons will result in hyperphagia and obesity. The studies offered in this application are designed to directly test the different components of this model.