The Role of Vsca1 in Erectile Function

描述(申请人提供)：勃起功能障碍(ED)的患病率随着社会老龄化和糖尿病患者数量的增加而增加，这些都是其发展的危险因素。勃起功能障碍对患者生活质量的影响通常被低估，但其对患者的重要性可以从目前可用的治疗方法的巨大市场中得到证明。我的实验室最近报道，Vcsal转录本(Variable Coding Sequence Protein A1)是三种ED模型中表达下调最严重的基因之一：糖尿病、年龄相关性和神经元性。因此，我们提出Vcsal可能是一种潜在的有机ED的标志物。此外，表达Vcsal的质粒的基因转移增加了老年大鼠的勃起功能，并且较高数量的质粒引起了异常勃起，表明Vcsal基因在勃起生理中起着直接作用。我们最近还证明了Vcsal的成熟多肽产物唾液酸吗啡可以直接恢复衰老大鼠的勃起功能。这使得我们提出了一种假设，即Vcsal对于正常的勃起功能是必不可少的，表达减少会导致勃起功能障碍，过度表达会导致勃起功能异常。这一假说将通过将表达Vcsal的质粒转移到患有ED的糖尿病动物的语料库中来验证，并确定这是否改善了勃起功能，或者更高的剂量会导致勃起。此外，我们还将使用腺病毒siRNA技术在大鼠体内进行Vcsal的基因敲除实验，以确定Vcsal的下调是否会导致ED。我们还将研究唾液酸吗啡直接恢复勃起功能的能力。我的团队和其他人最近发表的文章表明，唾液酸吗啡是一种有效的中性内肽酶(NEP)的生理拮抗剂。我们推测，唾液酸吗啡作为一种NEP抑制剂，可以松弛体部的平滑肌组织，从而改善勃起功能。高剂量的NEP抑制可能会导致异常勃起。我们将在体外对肌条进行研究，以确定抑制NEP是否可以诱导平滑肌松弛，以及抑制NEP是否可以改善老年大鼠的勃起功能。我们还将调查Vcsal的过度表达是否激活了与异常勃起相关的生化途径。有一种人类Vcsal同源基因(HSMRSA)，我们假设它在人类中具有类似的生理作用。我们将确定hSMRSA在ED患者的语体中是否下调，并确认hSMRSA对大鼠勃起功能的影响与Vcsal相同。这些研究将为勃起功能的生理学和病理生理学提供洞察力，并可能为治疗平滑肌疾病，如勃起功能障碍和异常勃起以及其他血管疾病提供新的靶点。Vcsal/hSMR3A的表达也可作为勃起功能的非主观指标。

DESCRIPTION (provided by applicant): Erectile dysfunction (ED) is increasing in prevalence with the ageing of society and with greater numbers of patients suffering from diabetes, which are risk factors for its development. The impact of ED on quality of life of patients is generally underestimated, but its significance to patients can be demonstrated by the huge market for currently available treatments. My laboratory recently reported that the Vcsal transcript (variable coding sequence protein a1) is one of the most down regulated genes in the corpora of rats in three models of ED; diabetic, age-related and neurogeniic. We therefore proposed that Vcsal could be a potential marker for organic ED. In addition, gene transfer of plasmids expressing Vcsal increased erectile function in ageing rats and higher amounts of plasmid caused priapism, suggesting a direct role of the Vcsal gene in erectile physiology. We also recently demonstrated that the mature peptide product of Vcsal, sialorphin, can directly restore erectile function in the ageing rat. This has led us to propose the hypothesis that Vcsal is essential for normal erectile function, that reduced expression results in ED and overexpression results in priapism. This hypothesis will be tested by gene transfer of plasmids expressing Vcsal into the corpora of diabetic animals with ED, and determining if this improves erectile function, or higher amounts causes priapism. In addition we will perform in vivo knockdown experiments of Vcsal in rats using adenovirus siRNA technology to determine if down regulation of Vcsal causes ED. We will also investigate the ability of sialorphin to directly restore erectile function. Recent publications by my group and others have shown that sialorphin is an efficient physiological antagonist of neutral endopeptidase (NEP). We hypothesize that the action of sialorphin as an NEP inhibitor induces relaxation of the smooth muscle tissue of corpora and thereby improves erectile function. Higher amounts of NEP inhibition may lead to priapism. We will perform studies of corporal smooth muscle strips in vitro to determine if inhibition of NEP can induce smooth muscle relaxation, and if NEP inhibition in ageing rats improves erectile function. We will also investigate if overexpression of Vcsal activates biochemical pathways associated with priapism. There is a human homoiogue of Vcsal (hSMRSA) which we hypothesize has a similar physiological role in humans. We will determine if hSMRSA is downregulated in the corpora of patients with ED and confirm that hSMRSA has the same effects on erectile function in rats as Vcsal. These studies will provide insight into the physiology and pathophysiology of erectile function and may suggest novel targets for treating smooth muscle diseases, such as ED and priapism and other vascular diseases. Vcsal/hSMR3A expression might also be used as a non-subjective marker of erectile function.