Cutaneous Hemangiomas and Signal Transduction

皮肤血管瘤和信号转导

基本信息

批准号：
8103817
负责人：
JACK L ARBISER
金额：
$ 25.93万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-09-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8103817
关键词：
1 year old Accounting Adverse effects Affect Angiogenesis Inhibitors Behavior Benign Biology Blood Vessels Carbazoles Cell Line Cell Proliferation Cells Cessation of life Child Childhood Clinical Common Neoplasm Cutaneous Data Deformity Development Diagnosis Disease Dose Effector Cell Endothelial Cells Event Funding Genes Growth Growth Factor Growth Inhibitors Heart failure Hemangioma Hemangiosarcoma Human Infant Infection Inflammation Inflammatory Interferon-alpha Interferons Kaposi Sarcoma Knock-out Lead Lesion Ligands Limb structure Lymphatic Malignant - descriptor Mediating Medical Medicine Modeling Morbidity - disease rate Mus Neoplasms Neuropathy Operative Surgical Procedures Output Oxygen Pain Paraffin Pathogenesis Physiological Play Prevention Process Publishing Regulator Genes Repression Role Signal Pathway Signal Transduction Signal Transduction Pathway Skin Steroids Structure Technology Testing Time Vascular remodeling WT1 gene angiogenesis carbazole efficacy testing functional disability honokiol in vivo infancy inhibitor/antagonist insight malformation migration notch protein novel novel therapeutic intervention prevent public health relevance receptor response skin disorder skin lesion small molecule triphenylmethane tumor

项目摘要

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.

描述（由申请人提供）：此申请的重点是血管瘤和相关血管生成的发病机理。血管瘤是儿童期最常见的皮肤血管病变，并且有5％的1岁婴儿。这些血管瘤可能会大大生长，并可能导致重要结构或高输出心力衰竭的压缩。大型血管瘤的治疗需要用类固醇或α干扰素和手术进行冗长的治疗。这些疗法与高水平的发病率有关，包括增长迟缓，感染和不可逆的神经病。这些血管瘤中有大量对治疗没有反应，导致死亡。血管畸形代表了童年的另一种皮肤病变，具有相当大的发病率。最初，血管畸形可能类似于血管瘤，但与血管瘤不同，血管畸形并不能自发消退。取而代之的是，它们倾向于随着时间的流逝而扩大，导致疼痛，畸形和肢体过度生长。与血管瘤不同，没有治疗血管畸形的药物。在最后一个资金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组合活性氧和AKT激活，而模型血管畸形细胞仅使用Akt激活。此外，我们发现在血管瘤中存在着重要的基因Wilms肿瘤1（WT-1），但在血管畸形中不存在。我们计划研究WT-1是否需要生理内皮回归。假设：信号转导的差异可以预测体内内皮肿瘤的行为。具体目的1。确定人血管病变中缺口配体和受体的存在以及凹配体在鼠Bend3血管瘤中的功能作用。具体目标2。确定NOX4的下游信号传导事件和血管病变中的活性氧。具体目的3。确定Wilms肿瘤1基因在血管畸形的内皮重塑和形成中的作用。该应用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，从本应用中描述的研究中获得的见解可能会导致通过信号转导调制的新型治疗方法来获得皮肤疾病。实际上，在先前的资金周期中提出的发现包括小分子血管生成抑制剂，例如honokiol，solenopsin，carbazole和triphenylmethanes。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，由于重要结构和畸形的功能障碍，因此引起了相当大的发病率。这些病变的生物学尚不完全了解，这些病变的治疗会导致药物和广泛的手术引起的副作用。该应用中的研究可能会为这些疾病开发新的治疗方法，这些疾病没有当前治疗的副作用，并且鉴于在其他疾病中可能发生相同的过程，例如皮肤炎症和肿瘤，这些研究的进展可能会导致对皮肤炎症和肿瘤的更好治疗。