Cutaneous Hemangiomas and Signal Transduction

描述（由申请人提供）：本申请的重点是血管瘤的发病机制和相关的血管生成。血管瘤是儿童时期最常见的皮肤血管病变，在1岁的婴儿中有5%存在。这些血管瘤可能长得很大，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时间的类固醇或干扰素治疗和手术。这些治疗与高发病率相关，包括生长迟缓、感染和不可逆的神经病变。这些血管瘤中有相当一部分对治疗无效，导致死亡。血管畸形是另一种发病率很高的儿童皮肤病变。最初，血管畸形可能类似于血管瘤，但与血管瘤不同的是，血管畸形不会自发消退。相反，它们会随着时间的推移而扩大，导致疼痛、畸形和肢体过度生长。与血管瘤不同，血管畸形没有医学治疗方法。在上一次资助期间进行的研究表明，血管瘤和血管畸形可以通过信号通路来区分。我们发现模型血管瘤细胞需要活性氧和akt的联合激活，而模型血管畸形细胞只需要akt的激活。此外，我们发现发育重要基因Wilms tumor 1 （WT-1）存在于血管瘤中，而不存在于血管畸形中。我们计划研究WT-1在生理性内皮退化中是否必要。假设：信号转导的差异可以预测体内内皮肿瘤的行为。具体目标确定Notch配体和受体在人血管病变中的存在以及Notch配体在小鼠弯曲血管瘤中的功能作用。具体目标2。确定nox4和活性氧在血管病变中的下游信号事件。具体目标3。目的：探讨Wilms肿瘤1基因在内皮重塑和血管畸形形成中的作用。本应用程序概述的研究将有助于我们对皮肤血管生成的基本理解。此外，从本应用中描述的研究中获得的见解可能通过信号转导调节导致新的皮肤疾病治疗方法。事实上，在之前的资助周期中发现的发现包括小分子血管生成抑制剂，如厚朴酚、螺线菌素、咔唑和三苯甲烷。

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.