Defective melanocortin signaling underlying T2D-associated erectile dysfunction

 描述（由申请人提供）：勃起功能障碍（艾德）是2型糖尿病的常见并发症，可损害高达75%的糖尿病男性的生活质量。艾德与胰岛素抵抗、肥胖和代谢综合征密切相关。本研究的长期目标是阐明糖尿病和糖尿病前期状态下艾德的发病机制。大脑通过启动性欲和控制自主勃起反应，在健康的勃起功能中起着关键作用。由产生α- MSH的POMC神经元和下游含有MC 3和4受体（MC 4 R）的神经元组成的黑皮质素途径对这些过程至关重要。然而，靶向MC受体的治疗剂具有改变血压和心率的缺点。本提案的目的是确定内源性α-MSH产生的减少是否可导致艾德，并鉴定POMC神经元投射到其上以独特地控制勃起功能的神经元回路。在POMC神经元投射到的催产素神经元上发现MC 4 R，并且施用a-MSH、MC 4 R激动剂或催产素在小鼠和人中增加性动机、激发性行为并引起阴茎勃起。中心假设是POMC神经元中的胰岛素和瘦素抵抗通过减少aMSH产生和催产素信号传导促进艾德。这一假设是根据申请人实验室提供的有力的初步数据提出的，并将以三个具体目标进行检验：1）确定POMC神经元中受损的胰岛素和瘦素信号传导是否改变勃起功能，2）确定恢复神经元胰岛素和瘦素敏感性和α-MSH产生是否改善性表现，和3）确定下游催产素回路是否介导α-MSH对勃起功能的作用。根据第一个目标，新的细胞类型特异性工具将被用来允许急性神经元操作，以检查POMC特异性胰岛素和瘦素抵抗在艾德在一个独特的小鼠糖尿病前期模型中的作用。在第二个目标中，申请人将确定重新激活下丘脑瘦素和胰岛素途径是否恢复正常的性功能，并在由饮食诱导的肥胖引起的中枢胰岛素和瘦素抵抗的情况下提供潜在的治疗策略。在第三个目标下，申请人将使用药物遗传学来确定下游催产素回路是否介导α-MSH对勃起功能的影响，以检查该途径是否是必要的和充分的。然后将采用完善的cre依赖性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的有缺陷的黑皮质素信号传导的研究。鉴于黑皮质素途径参与调节血压，肥胖和血糖控制，拟议的研究有可能指导开发新的有效疗法，而没有副作用，可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.