Defective melanocortin signaling underlying T2D-associated erectile dysfunction

T2D 相关勃起功能障碍潜在的黑皮质素信号传导缺陷

基本信息

批准号：
8888203
负责人：
Jennifer Wootton Hill
金额：
$ 33.63万
依托单位：
UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8888203
关键词：
Acute Address Adverse effects Affect Agonist Area Behavior monitoring Behavioral Blood Pressure Body Weight Brain Complication Copulation Data Designer Drugs Development Diabetes Mellitus Diabetic mouse Diet Disadvantaged Disease Erectile dysfunction Exhibits Failure Fasting Frequencies Goals Health Heart Rate Hormonal Human Hyperglycemia Hypertension Hypothalamic structure Individual Insulin Insulin Receptor Insulin Resistance Knowledge Laboratories Lead Leptin Leptin resistance Life Maps Measures Mediating Melanocortin 3 Receptor Melanocortin 4 Receptor Metabolic syndrome Monitor Motivation Mus Neurons Non-Insulin-Dependent Diabetes Mellitus Obesity Output Oxytocin Pathogenesis Pathway interactions Patients Penile Erection Performance Pharmaceutical Preparations Pharmacogenetics Physiological Play Population Prediabetes syndrome Process Production Protein Tyrosine Phosphatase Quality of life Receptor Signaling Research Resistance Rodent Role Sensory Sex Behavior Sex Functioning Signal Transduction Spinal Cord Technology Testing Time Tissues Tracer Viagra Viral alternative treatment base blood pressure regulation cell type diabetic diabetic patient drug production effective therapy glycemic control impaired glucose tolerance improved improved functioning inhibitor/antagonist leptin receptor male men mouse model neuronal circuitry non-diabetic novel novel strategies paraventricular nucleus phosphoric diester hydrolase pressure prevent public health relevance receptor reproductive response therapeutic target tool treatment strategy

项目摘要

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.

描述（通过应用程序）：勃起功能障碍（ED）是2型糖尿病的经常汇编，其中5％的糖尿病与胰岛素抵抗，肥胖和代谢综合征密切相关。通过启动性desie和控制A -MSH和下游MC3和4受体（MC4R）的神经元，通过启动性desie和控制勃起的勃起反应来理解ED的发病机理受体具有改变血压和心率的缺点。 A-MSH或催产素的投射会增加性动机，引起性行为，并在小鼠和人类中引起阴茎勃起。该假设已根据实验室中产生的强初步数据提出，并将用三个特定AMS进行测试：1）POMC神经元中的D瘦素信号传导改变了勃起功能，2）确定是否恢复神经元胰岛素和瘦素敏感性以及A-MSH是否恢复生产改善了性能力，3）目标，新型细胞类型特异性工具遗嘱允许急性神经元操作检查pOMC特异性胰岛素和瘦素在独特的糖尿病小鼠中的作用。胰岛素可以恢复正常的性功能，并在饮食引起的肥胖症引起的中央诱导蛋白立场的Casse中提供潜在的治疗策略。这是必要的，然后使用镇流的福特。经过的研究指导了这些患者的副作用和整体健康的副作用。