Cutaneous Hemangiomas and Signal Transduction

描述（由申请人提供）：本申请关注血管瘤发病机制和相关血管生成。血管瘤是儿童期最常见的皮肤血管病变，在1岁的婴儿中占5%。这些血管瘤可能会生长到很大的尺寸，并可能导致重要结构的压迫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α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没有反应，导致死亡。血管畸形是另一种发病率相当高的儿童皮肤病变。最初，血管畸形可能类似于血管瘤，但与血管瘤不同，血管畸形不会自发消退。相反，它们往往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。在上一个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激活的组合，而模型血管畸形细胞仅使用akt激活。此外，我们发现，发育重要的基因Wilms肿瘤1（WT-1）是目前在血管瘤，但不是在血管畸形。我们计划研究WT-1是否是生理性内皮退化所必需的。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1。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bend 3血管瘤中的功能作用。具体目标2。探讨nox 4与活性氧在血管病变中的下游信号传导。具体目标3。探讨肾母细胞瘤1基因在内皮重塑和血管畸形形成中的作用。本申请中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，从本申请中描述的研究中获得的见解可能导致通过信号转导调节治疗皮肤疾病的新方法。事实上，在前一个资助周期中发现的包括小分子血管生成抑制剂，如和诺明、solenopsin、咔唑和三苯基甲烷。 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损害和畸形，导致相当多的发病率。这些病变的生物学尚不完全清楚，并且这些病变的治疗由于药物和广泛的手术而引起副作用。本申请中的研究有可能为这些疾病开发新的治疗方法，这些方法没有当前治疗的副作用，并且考虑到相同的过程可能发生在其他疾病中，例如皮肤炎症和肿瘤，这些研究的进展可能会导致更好的皮肤炎症和肿瘤治疗。

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.