LOSARTAN IMPROVES VENTILATION IN DYSTROPHIC HAMSTERS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者的研究机构。 BIO 14.6仓鼠是肢带型肌营养不良症的动物模型，表现出通气受损，导致低氧血症，可能加剧心脏和骨骼肌功能障碍。该动物模型还表现出血管紧张素II和血管紧张素AT 1受体的水平。该系统不仅作为经典的内分泌系统具有活性，而且还存在于中枢神经系统中，在中枢神经系统中其调节CNS功能，包括多巴胺能神经元完整性、酪氨酸羟化酶表达、多巴胺能释放和多巴胺能受体功能。本提案的目的是检验以下假设：长期给予氯沙坦（一种AT 1受体拮抗剂）将使营养不良仓鼠的通气改善1。改善脑组织结构和功能（如Cohn及其同事最近的研究所建议的）和2.减少TH表达、多巴胺产生和使多巴胺受体功能正常化。另一个可能影响通气的因素是氯沙坦增强营养不良仓鼠的心血管功能。虽然这是有据可查的，但我们还将确定氯沙坦是否也能改善营养不良心脏的结构变化，如纤维化增加。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The BIO 14.6 hamster, an animal model of limb-girdle muscular dystrophy demonstrates compromised ventilation resulting in hypoxemia that may exacerbate cardiac and skeletal muscle dysfunction. This animal model also exhibits levels of angiotensin II and angiotensin AT1 receptors. Not only is this system active as a classic endocrine, it is also found in the central nervous system where it modulates CNS function including dopaminergic neuron integrity, tyrosine hydroxylase expression, dopaminergic release and dopaminergic receptor function. The purpose of this proposal is to test the hypothesis that chronic losartan (an AT1 receptor antagonist) administration will improve ventilation in dystrophic hamsters by 1. improving diaphragmatic structure and function (as suggested by the recent study by Cohn and colleagues) and 2. decreasing TH expression, dopamine production, and normalizing dopamine receptor function. Another factor that may affect ventilation is that losartan augments cardiovascular function in dystrophic hamsters. Although this is well documented, we will also determine if structural changes in the dystrophic heart such as increased fibrosis are also improved by losartan function.