Prevention and Treatment of Impotence

勃起功能障碍（艾德）是美国常见的健康问题。 美国患有艾德，每年诊断出数万例新病例，除了是一个 严重的生活质量问题艾德也是潜在致死性疾病（如冠状动脉）的前哨事件 疾病 阴茎勃起是一个复杂的过程，涉及心理，激素，神经和血管输入。任何 影响相关系统的疾病或病症可导致ED。 美国包括糖尿病、高血压、高脂血症、心脏病、烟草使用、盆腔手术， 和肾衰竭 在当前的资助期内，我们研究了生长因子对勃起神经损伤和恢复的调节。 我们证明了脑源性神经营养因子（BDNF）在阴茎海绵体切除后表达上调， 神经损伤，并可以通过逆行轴突运输到主要盆神经节（MPG）。我们 证明BDNF和VEGF在体外促进神经突生长，并且这些药物的组合 在促进源自大鼠的MPG的神经突生长方面非常有效。 在体内研究中，我们证明了海绵体内注射BDNF和血管内皮细胞， 生长因子（VEGF）使大鼠海绵体神经损伤后的艾德最小化。我们进一步证明， BDNF激活这些动物MPG和阴茎中的JAK/STAT通路，有两个不同的时间段， 增加激活。免疫组织化学和分子生物学研究表明， 和阴茎内含nNOS神经纤维的再生。这种神经保护作用可能 在恢复这些动物的勃起功能中起着关键作用。对勃起功能有类似的保护作用， 用海绵体内注射胰岛素样生长因子-1（IGF-1），neurturin， FK 1706和生长分化因子5（GDF-5）。不幸的是， 获得用于这些化合物的人体研究的人级生长因子是极其困难的。 随后，我们将实验室的努力集中在ED的干细胞治疗上。 海绵体内注射胚胎干细胞在大鼠海绵体神经损伤后保留勃起功能。 由于对胚胎干细胞使用的担忧，我们随后选择专注于自体体干细胞 细胞我们在脂肪干细胞生物学方面有了几项重要发现。 基于已知干细胞标记物的免疫组织化学研究，这些脂肪来源的干细胞（ADSC） 已被证明具有广泛的分化能力。我们已经证明，ADSC 有能力分化成神经元样细胞，内皮细胞，肌肉细胞，白蛋白产生细胞， 肝细胞和产生胰岛素的β细胞。我们还发现成纤维细胞 生长因子2（FGF 2）在ADSC中表达，但在细胞增殖后， 因此，我们得出结论，FGF 2在调节ADSC分化中起重要作用。 ADSC分化后，几种特异性microRNA表达上调，提示microRNA可能是ADSC分化后的一个重要因素。 对于微调分化反应非常重要。 在大鼠海绵体神经挤压损伤时，海绵体内注射自体ADSC， 已被证明可以增强损伤后的勃起反应;在脊髓损伤后的脊髓中检测到增强的nNOS神经纤维染色。 这些治疗动物的阴茎组织。ADSC也能有效逆转艾德性ED和降低细胞凋亡。 通过海绵体内注射接受该治疗的糖尿病动物中的细胞凋亡标记物。 在下一个资助期内，我们建议研究FGF 2和微血管内皮细胞对ADSC分化的调节作用。 RNA。我们还将进一步研究这些细胞作为治疗ED的有效性和长期安全性。 最终目标是使用ADSC不仅治疗各种类型的艾德，而且治疗其他退行性疾病， 如糖尿病、尿失禁和心血管疾病。

Erectile dysfunction (ED) is a common health problem in the U.S. Approximately 20 million men in the United States suffer from ED with tens of thousands of new cases diagnosed every year, in addition to being a serious quality of life issue ED is also a sentinel event for potentially lethal conditions such as coronary artery disease. Penile erection is a complex process involving psychological, hormonal, neural, and vascular input. Any disease or condition that affects the relevant systems can cause ED. The most common risk factors for ED in the United States include diabetes, hypertension, hyperiipidemia, cardiac disease, tobacco use, pelvic surgery, and renal failure. In the current funding period we studied growth factor regulation of erectile nerve injury and recovery. We demonstrated that brain derived neurotrophic factor (BDNF) is upregulated in the penis after cavernous nerve injury and can be transported by retrograde axonal transport to the major pelvic ganglion (MPG). We demonstrated that BDNF and VEGF enhance neurite growth in vitro and that the combination of these agents is very effective at enhancing neurite growth from MPGs derived from rats. In in vivo studies, we demonstrated that intracavernous injection of BDNF and vascular endothelial growth factor (VEGF) minimized ED after cavernous nerve injury in rat models. We further demonstrated that BDNF activates the JAK/STAT pathway in the MPG and penis of these animals with two distinct periods of increased activation. Immunohistochemistry and molecular biology studies indicated increased preservation and regeneration of nNOS containing nerve fibers in the penis of these rats. This neuroprotective effect likely plays a key role in restoring erectile function in these animals. Similar protective effects on erectile function and nNOS nerves were noted with intracavernous injection of insulin-like growth factor-1 (IGF-1), neurturin, FK1706, and Growth and Differentiation Factor 5 (GDF-5) at the time of cavernous nerve injury. Unfortunately, obtaining human grade growth factors for a human study ofthese compounds was prohibitively difficult. We have subsequently focused the efforts of our lab on stem cell therapy for ED. We demonstrated that intracavernous injection of embryonic stem cells preserves erectile function after cavernous nerve injury in rats. Due to concerns about embryonic stem cell use, we subsequently elected to focus on autologous somatic stem cells. We have made several important discoveries on the biology of stem cells derived from adipose tissue. Based on immunohistochemical studies for known stem cell markers, these adipose derived stem cells (ADSC) have been demonstrated to have a wide range of differentiation capacity. We have demonstrated that ADSC have the capacity to differentiate into neuron-like cells, endothelial cells, muscle cells, albumin-producing hepatocytes and insulin-producing beta cells when properly induced. We have also discovered that fibroblast growth factor 2 (FGF2) is expressed in ADSC but expression of the protein goes down after cellular differentiation, leading us to conclude that FGF2 plays an important role in regulating ADSC differentiation. Several specific microRNAs are upregulated in ADSC after differentiation, suggesting that microRNA may be very important in fine tuning the differentiation response. Intracavernous injection of autologous ADSC at the .time of cavernous nerve crush injury in rats has been shown to enhance erectile response post-injury; enhanced nNOS nerve fiber staining was detected in the penile tissues of these treated animals. ADSC were also effective in reversing ED and decreasing cellular markers for apoptosis in diabetic animals who received this treatment by intracavernous injection. In the next funding period, we propose to study regulation of ADSC differentiation by FGF2 and micro RNAs. We will also further study the efficacy and long-term safety of these cells as a treatment for ED. Our ultimate goal is to use ADSC to treat not only various types of ED but also other degenerative diseases such as diabetes, urinary incontinence, and cardiovascular disease.