Cutaneous Hemangiomas and Signal Transduction

皮肤血管瘤和信号转导

基本信息

批准号：
8856496
负责人：
JACK L ARBISER
金额：
$ 34.32万
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 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8856496
关键词：
Address Adrenergic beta-Antagonists Adverse effects Agreement Angiogenesis Inhibitors Angiopoietin-2 Animals Aortic coarctation Behavior Blood Vessels Bradycardia Brain Cell model Cells Cervical Child Clinical Clinical Treatment Clinical Trials Combined Modality Therapy Congenital Heart Defects Cutaneous Disease Down-Regulation Doxorubicin Drug usage Dyes Endothelial Cells Eosine Yellowish Exhibits Eye FDA approved Face Funding Glioblastoma Growth Health Hemangioma Hemangiosarcoma Hospitalization Human Hypotension In Vitro Infant Inhibitory Concentration 50 Isomerism Kaposiform Hemangioendothelioma Lead Legal patent Lesion Licensing Lymphangioma Lymphatic Malignant Vascular Neoplasm Modeling Mus NADPH Oxidase Neoplasms Optics Outpatients Oxygen Palladium Paper Pathologic Neovascularization Pathway interactions Patients Pharmacologic Substance Phosphotransferases Posterior Fossa Propranolol Proteins Ras Inhibitor Rattus Research Risk Role SRC gene Science Signal Pathway Signal Transduction Sirolimus Stroke Syndrome Therapeutic angiogenesis blood pressure reduction cerebrovascular endoplasmic reticulum stress honokiol human FRAP1 protein human NOS3 protein improved in vivo infancy inhibitor/antagonist insight malformation melanoma member mouse model myristoylation novel novel strategies novel therapeutic intervention prevent signal processing small molecule src-Family Kinases translational medicine triphenylmethane tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): This application focuses on using the information gained during the previous cycle of this proposal to the treatment of hemangiomas, vascular malformations and malignant vascular tumors. We have demonstrated three different signaling processes that underlie the three classes of vascular lesions, and have come up with novel approaches to treat these lesions. In particular, we have found that hemangiomas of infancy use a reactive oxygen/Akt/Angiopoietin-2 signaling pathway and have shown that inhibitors of this pathway are efficacious in the treatment of hemangiomas in both mice and humans. Second, we have found that many vascular malformations use an Akt dependent but reactive oxygen independent pathway. Given that agents that induce endoplasmic reticulum stress (ER stress) downregulate Akt, therapeutic induction of ER stress may lead to novel therapies for vascular malformations. Indeed, we have found that honokiol, a small molecule angiogenesis inhibitor, is a potent inducer of ER stress, as well as an inhibitor of ras signaling. Finally, we have found a novel compound, tris DBA palladium, which blocks src family kinase signaling by blocking myristoylation. Of importance, tris DBA palladium exhibits activity in vivo against tumor xenografts. Given that hemangiomas likely require src family kinase activity, and that tris DBA palladium prevents src family kinase activation through inhibition of myristoylation, tris DBA palladium might be a novel therapy for hemangiomas. Studies performed during the last funding period have suggested that hemangiomas and vascular malformations can be distinguished by signaling pathways. Interestingly, propranolol, a beta blocker, has become the treatment of choice for large hemangiomas of infancy. Propranolol is also an inhibitor of NADPH oxidase, thus its activity may be independent of beta blockade, and thus treatment of hemangiomas may be accomplished without the hospitalization associated with beta blockade side effects in infants. We may be able to accomplish this by using optically active isomers that are inactive as beta blockers but active as NADPH oxidase inhibitors. Patients with hemangiomas and PHACE (P - Posterior fossa abnormalities, H - Hemangioma(s) of the cervical facial region, A - Arterial cerebrovascular anomalies, C - Cardiac defects, aortic coarctation and other aortic abnormalities, E - Eye anomalies) syndrome are at increased risk of stroke, so an agent that doesn't lower blood pressure would be of great benefit to these children. Hypothesis: Differences in signal transduction can guide the treatment of endothelial neoplasms in vivo. Specific Aim 1: To evaluate the activity of optical isomers of beta blockers as antihemangioma agents. Specific Aim 2: To evaluate the combination of ER stress and mTOR blockade against vascular malformation models. Specific Aim 3: To determine the role of myristoyltransferase inhibition on hemangioma growth in vivo.

描述（由申请人提供）：本申请的重点是使用本提案上一个周期中获得的信息，以治疗血管瘤，血管畸形和恶性血管肿瘤。我们已经证明了三种不同的血管病变的信号传导过程，并提出了治疗这些病变的新方法。特别是，我们发现婴儿期血管群使用活性氧/Akt/Angiopoietin-2信号通路，并表明该途径的抑制剂在治疗小鼠和人类中血管瘤有效。其次，我们发现许多血管畸形使用AKT依赖性但反应性氧无关的途径。鉴于诱导内质网应激（ER应激）下调AKT的药物，ER应激的治疗诱导可能会导致新的血管畸形疗法。实际上，我们发现小分子血管生成抑制剂Honokiol是ER应激的有效诱导剂，也是RAS信号传导的抑制剂。最后，我们发现了一种新颖的化合物Tris DBA钯，该化合物通过阻止肉豆蔻酰化来阻断SRC家族激酶信号传导。重要的是，Tris DBA钯在体内对肿瘤异种移植物的活性。鉴于血管瘤可能需要SRC家族激酶活性，并且TRIS DBA钯通过抑制肉豆蔻酰化来防止SRC家族激酶激活，因此TRIS DBA钯可能是对血管瘤的新疗法。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。有趣的是，β受体阻滞剂普萘洛尔已成为大型婴儿血管瘤的首选治疗方法。普萘洛尔也是NADPH氧化酶的抑制剂，因此其活性可能独立于β封锁，因此可以在婴儿中与β封锁副作用相关的住院治疗，因此可以完成血管瘤的治疗。我们可能能够通过使用无活性的β受体阻滞剂但活性为NADPH氧化酶抑制剂的光学活性异构体来实现这一目标。患有血管瘤和牙齿的患者（P-宫颈后部异常，H-颈椎面部的血管瘤（S），A-动脉脑血管异常，C-心脏缺陷，心脏缺陷，主动脉核和主动脉arc骨和其他主动脉异常的影响，e-肿胀的效果较大，是较大的疾病，而不是较高的效果，这是较大的症状，同样是综合体系的综合性，同样是综合体系的综合性，而综合体系的综合性，综合体系的综合性，这些孩子。假设：信号转导的差异可以指导体内内皮肿瘤的治疗。特定目的1：评估β受体阻滞剂的光学异构体作为抗障碍药物的活性。特定目的2：评估与血管畸形模型的ER应力和MTOR阻滞的组合。具体目的3：确定肉豆蔻酰转移酶抑制对体内血管瘤生长的作用。