Defective melanocortin signaling underlying T2D-associated erectile dysfunction

 描述(申请人提供)：勃起功能障碍(ED)是2型糖尿病的一种常见并发症，高达75%的糖尿病男性患者的生活质量受到影响。勃起功能障碍与胰岛素抵抗、肥胖和代谢综合征密切相关。这项研究的长期目标是阐明糖尿病和糖尿病前期状态下ED的发病机制。大脑通过启动性欲望和控制自主神经勃起反应，在健康的勃起功能中发挥关键作用。黑素皮质素通路由产生α-MSH的POMC神经元和下游含有MC3和4受体(MC4R)的神经元组成，在这些过程中起着关键作用。然而，针对MC受体的治疗药物有改变血压和心率的缺点。该方案的目的是确定内源性α-MSH的产生减少是否会导致勃起功能障碍，并确定POMC神经元投射到的神经元回路，以独特地控制勃起功能。在POMC神经元投射到的催产素神经元上发现了MC4R，给予α-MSH、MC4R激动剂或催产素增加了性动机，引出了性行为，并导致了小鼠和人类的阴茎勃起。中心假说是POMC神经元中的胰岛素和瘦素抵抗通过减少aMSH的产生和催产素信号来促进ED。这一假设是基于申请者实验室提供的强有力的初步数据提出的，并将以三个具体目标进行测试：1)确定POMC神经元中受损的胰岛素和瘦素信号是否改变勃起功能；2)确定恢复神经元胰岛素和瘦素敏感性以及a-MSH产生是否改善性行为；以及3)确定催产素下游回路是否介导a-MSH对勃起功能的影响。在第一个目标下，将使用新的细胞类型特异性工具来允许急性神经元操作，以在一种独特的糖尿病前期小鼠模型中检测POMC特异性胰岛素和瘦素抵抗在ED中的作用。在第二个目标中，申请者将确定重新激活下丘脑瘦素和胰岛素通路是否恢复了正常的性功能，并提供了一种潜在的治疗策略，用于治疗由饮食诱导的肥胖引起的中枢胰岛素和瘦素抵抗。在第三个目标下，申请者将使用药物遗传学来确定催产素下游回路是否介导了a-MSH对勃起功能的影响，以检查这一途径是否必要和充分。然后将使用一种成熟的依赖于cre的病毒示踪剂来绘制下游电路。这些研究的基本原理是，它们将是第一个解决糖尿病是否伴随着可能导致或加剧ED的黑素皮质素信号缺陷的问题。肥胖和2型糖尿病男性人数的增加使这项研究具有非常重要的意义。鉴于黑素皮质素通路参与调节血压、肥胖和血糖控制，拟议的研究有可能指导开发新的、有效的、无副作用的治疗方法，以改善这些患者的生活质量和整体健康。

 DESCRIPTION (provided by applicant): Erectile dysfunction (ED) is a frequent complication of type 2 diabetes that impairs quality of life for up to 75% of men with diabetes. ED strongly correlates with insulin resistance, obesity, and the metabolic syndrome. The long-term goal of this research is to elucidate the poorly understood pathogenesis of ED in diabetic and pre- diabetic states. The brain serves a key role in healthy erectile function by initiating sexual desie and by controlling autonomic erectile responses. Melanocortin pathways, consisting of POMC neurons that produce a- MSH and downstream MC3 and 4 receptor (MC4R)-containing neurons, are critical for these processes. However, therapeutics targeting MC receptors have the disadvantage of altering blood pressure and heart rate. The objective of this proposal is to determine if reduced endogenous a-MSH production can lead to ED and to identify the neuronal circuitry to which POMC neurons project to uniquely control erectile function. MC4Rs are found on oxytocin neurons to which POMC neurons project, and administration of a-MSH, MC4R agonists, or oxytocin increases sexual motivation, elicits sexual behaviors, and causes penile erection in mice and humans. The central hypothesis is that insulin and leptin resistance in POMC neurons promotes ED by reducing aMSH production and oxytocin signaling. This hypothesis has been formulated on the basis of strong preliminary data produced in the applicants' laboratories and will be tested with three specific aims: 1) Determine whether impaired insulin and leptin signaling in POMC neurons alters erectile function, 2) Determine whether restoring neuronal insulin and leptin sensitivity and a-MSH production improves sexual performance, and 3) Determine whether downstream oxytocin circuitry mediates the effects of a-MSH on erectile function. Under the first aim, novel cell type-specific tools will be used to allow acute neuronal manipulation to examine the role of POMC-specific insulin and leptin resistance in ED in a unique mouse model of prediabetes. In the second aim, the applicants will then determine whether reactivating hypothalamic leptin and insulin pathways restores normal sexual function and offers a potential treatment strategy in cases of central insulin and leptin resistance caused by diet-induced obesity. Under the third aim, the applicants will determine whether downstream oxytocin circuitry mediates the effects of a-MSH on erectile function using pharmacogenetics to examine whether this pathway is necessary and sufficient. A well-established cre-dependent viral tracer will then be employed to map downstream circuitry. The rationale for these studies is that they will be the first to address whether diabetes is accompanied by defective melanocortin signaling that may cause or exacerbate ED. The rising number of men with obesity and type 2 diabetes makes this research highly significant. Given the involvement of melanocortin pathways in regulating blood pressure, obesity, and glycemic control, the proposed research has the potential to guide the development of novel and effective therapies devoid of side effects that improve both the quality of life and overall health of these patients.