Cutaneous Hemangiomas and Signal Transduction

描述(申请人提供)：本申请侧重于血管瘤的发病机制和相关的血管生成。血管瘤是儿童最常见的皮肤血管病变，1岁时5%的婴儿会出现血管瘤。这些血管瘤可能生长到很大，并可能导致重要结构受压或高输出量心力衰竭。大血管瘤的治疗需要长期的类固醇或α-干扰素治疗，以及手术。这些治疗与高发病率相关，包括生长迟缓、感染和不可逆转的神经病。这些血管瘤中有相当一部分对治疗没有反应，导致死亡。血管畸形是儿童时期的另一种皮肤损害，发病率相当高。最初，血管畸形可能类似于血管瘤，但与血管瘤不同，血管畸形不会自发退化。相反，它们往往会随着时间的推移而增大，导致疼痛、畸形和肢体过度生长。与血管瘤不同，血管畸形没有药物治疗。在上一次资助期间进行的研究表明，可以通过信号通路来区分血管瘤和血管畸形。我们发现，模型血管瘤细胞需要活性氧和AKT激活的组合，而模型血管畸形细胞只使用AKT激活。此外，我们还发现发育重要的基因Wilms Tumor 1(WT-1)存在于血管瘤中，但不存在于血管畸形中。我们计划调查WT-1是否是生理性内皮细胞退化所必需的。假设：信号转导的不同可以预测体内血管内皮细胞肿瘤的行为。具体目的1.确定Notch配体和受体在人类血管病变中的存在以及Notch配体在小鼠Bend3血管瘤中的功能作用。具体目的2.确定血管病变中NOX4和活性氧的下游信号转导事件。具体目的3.探讨Wilms肿瘤1基因在血管内皮细胞重构和血管畸形形成中的作用。本申请概述的研究将有助于我们对皮肤血管生成的基本了解。此外，从本申请中描述的研究中获得的见解可能会导致通过信号转导调节来治疗皮肤病的新方法。事实上，在前一个资助周期中的发现包括小分子血管生成抑制剂，如和厚朴酚、Solenopsin、咔唑和三苯甲烷。 公共卫生相关性：血管瘤和血管畸形是儿童最常见的血管病变，由于重要结构的功能障碍和畸形而导致相当大的发病率。这些损害的生物学还不完全清楚，这些损害的治疗由于药物和广泛的手术而引起副作用。这项申请中的研究有可能为这些疾病开发新的治疗方法，这些方法不会有当前治疗方法的副作用，而且考虑到同样的过程可能发生在其他疾病中，如皮肤炎和肿瘤，这些研究的进展可能会带来更好的皮肤炎和肿瘤治疗方法。

DESCRIPTION (provided by applicant): This application focuses on the mechanisms of pathogenesis of hemangiomas and associated angiogenesis. Hemangiomas are the most common cutaneous vascular lesions of childhood, and are present in 5 percent of infants at 1 year of age. These hemangiomas may grow to large sizes and may result in compression of vital structures or high output cardiac failure. Treatment of large hemangiomas requires lengthy treatment with steroids or alpha interferon, and surgery. These treatments are associated with a high level of morbidity, including growth retardation, infection, and irreversible neuropathy. A significant number of these hemangiomas do not respond to treatment, resulting in death. Vascular malformations represent another skin lesion of childhood with considerable morbidity. Initially, vascular malformations may resemble hemangiomas, but unlike hemangiomas, vascular malformations do not spontaneously regress. Instead, they tend to enlarge with time, causing pain, deformity, and limb overgrowth. Unlike hemangiomas, there are no medical treatments for vascular malformations. Studies performed during the last funding period have suggested that hemangiomas and vascular malformations can be distinguished by signaling pathways. We have found that model hemangioma cells require a combination of reactive oxygen and akt activation, while model vascular malformation cells use akt activation alone. In addition, we have found that the developmentally important gene Wilms tumor 1 (WT-1) is present in hemangiomas, but not in vascular malformations. We plan to investigate whether WT-1 is necessary for physiologic endothelial regression. Hypothesis: Differences in signal transduction can predict the behavior of endothelial neoplasms in vivo. Specific Aim 1. To determine the presence of Notch ligands and receptors in human vascular lesions and functional role of Notch ligands in murine bend3 hemangiomas. Specific Aim 2. To determine the downstream signaling events of nox4 and reactive oxygen in vascular lesions. Specific Aim 3. To determine the role of the Wilms tumor 1 gene in endothelial remodeling and formation of vascular malformations. The studies outlined in this application will contribute to our basic understanding of cutaneous angiogenesis. In addition, insights gained from the studies described in this application may lead to novel therapeutic approaches to cutaneous disease through signal transduction modulation. Indeed, discoveries made during the prior funding cycle include small molecule angiogenesis inhibitors such as honokiol, solenopsin, carbazole, and triphenylmethanes. PUBLIC HEALTH RELEVANCE: Hemangiomas and vascular malformations are the most common vascular lesions of children, and cause a considerable deal of morbidity because of functional impairment of vital structures and deformity. The biology of these lesions is not fully understood, and the treatment of these lesions causes side effects due to medicines and extensive surgery. The studies in this application have the potential of developing new treatments for these disorders that do not have the side effects of current therapy and given that the same processes may be occurring in other disorders, such as skin inflammation and tumors, advances from these studies may lead to better treatments for skin inflammation and tumors.