Mechanisms underlying leptin's effects on adult hippocampal neurogenesis

瘦素影响成人海马神经发生的机制

• 批准号: 7487670
• 负责人: Jacob C Garza
• 金额: $ 2.63万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7487670
• 关键词: Address; Adipocytes; Adult; Affect; Antidepressive Agents; Cell Proliferation; Cognitive; Cognitive deficits; Data; Disease; Docking; Generations; Hippocampus (Brain); Human; In Vitro; Knockout Mice; Leptin; Link; MAP Kinase Gene; MEKs; Mediating; Mental Depression; Mood Disorders; Moods; Neurons; Pathway interactions; Play; Protein Isoforms; Proteins; Proto-Oncogene Proteins c-akt; Purpose; Regulation; Role; Signal Transduction; Signal Transduction Pathway; Site; Stem cells; System; Testing; United States; base; dentate gyrus; in vivo; inhibitor/antagonist; leptin receptor; mouse model; neurogenesis; peptide hormone; therapeutic target

DESCRIPTION (provided by applicant): Mood and cognitive orders such as depression affect more than 20 million people each year in the United States. Current therapies have limited efficacy and therefore, it is imperative that we continue to search for new targets to treat these disorders. Adult hippocampal neurogenesis has been implicated in disorders. It has been demonstrated that the generation of new neurons in the hippocampus is essential for efficacy of current antidepressants (Santarelli et al., 2003). Recently, our lab identified leptin as a potential antidepressant (Lu et al., 2006). We have demonstrated that leptin treatment has a neurogenic effect in the hippocampus. The purpose of this proposal is to determine the role that leptin receptor activity in the hippocampus plays in the regulation of adult hippocampal neurogenesis. We hypothesize that leptin receptor activity in the hippocampus regulates neurogenic activity by the activation of specific intracellular mechanisms. To address this we devised the following specific aims. Specific Aim 1 will determine the functional role of LepRb activity in the hippocampus in adult hippocampal neurogenesis.We will address this by generating conditional knockout mice lacking LepRb in the hippocampus using the cre-loxp system. We will determine if LepRb in the hippocampus regulates basal neurogenic activity and mediates the pharmacological effect of leptin on neurogenesis. Specific Aim 2 will identify signal transduction pathways underlying leptin's effect on neurogenesis. LepRb has been linked to activation of multiple intracellular signal transduction pathways, including JAK/STAT, MAPK, and PI3K-AKT. This aim will examine specific signal transduction mechanisms involved in leptin's effects on hippocampal cell proliferation and differentiation both in vitro and in vivo. To address this, first we will establish adult hippocampal stem cell culture to determine whether treatment with specific inhibitors of STATS, MAPK, and Akt can block leptin's effects on neurogenesis. Next will determine whether the signal transduction pathways identified in vitro also mediate leptin's effects in vivo. Identifying the mechanisms by which leptin regulates neurogenesis will reveal potential therapeutic targets for the treatment of cognitive and mood disorders.

描述（由申请人提供）：在美国，情绪和认知秩序（例如抑郁症）每年影响超过2000万人。当前的疗法的功效有限，因此，我们必须继续寻找治疗这些疾病的新目标。成年海马神经发生与疾病有关。已经证明，海马中新神经元的产生对于当前抗抑郁药的功效至关重要（Santarelli等，2003）。最近，我们的实验室将瘦素确定为潜在的抗抑郁药（Lu等，2006）。我们已经证明瘦素治疗对海马有神经源作用。该建议的目的是确定瘦素受体活性在海马中发挥作用在成年海马神经发生中的作用。我们假设海马中的瘦素受体活性通过特定细胞内机制的激活来调节神经源性。为了解决这个问题，我们设计了以下特定目标。具体的目标1将确定LEPRB活性在成年海马神经发生中海马中的功能作用。我们将使用CRE-LOXP系统在海马中生成条件敲除小鼠来解决这一问题。我们将确定海马中的LEPR是否调节基础神经源性活性，并介导瘦素对神经发生的药理作用。特定的目标2将识别瘦素对神经发生的影响的信号转导途径。 LEPRB已与包括JAK/STAT，MAPK和PI3K-AKT在内的多个细胞内信号转导途径的激活有关。该目标将检查瘦素对海马细胞增殖和分化的影响的特定信号转导机制，包括体外和体内。为了解决这个问题，首先，我们将建立成年的海马干细胞培养物，以确定使用特定的Stats，MAPK和AKT的特定抑制剂治疗是否可以阻止瘦素对神经发生的影响。接下来将确定在体外鉴定的信号转导途径是否还介导了体内瘦素的作用。确定瘦素调节神经发生的机制将揭示潜在的治疗靶标，以治疗认知和情绪障碍。