NEUROFIBROMATOSIS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 2型神经纤维瘤病(NF2)是一种常染色体显性遗传性疾病，患者常发生多种病变，包括周围生长缓慢的脊髓神经鞘瘤和皮肤神经鞘瘤，以及脑和脊柱的脑膜瘤和胶质瘤。尽管与NF2相关的神经鞘瘤和脑膜瘤通常是良性和局灶性的，但通过压迫关键的脑神经和结构，或阻断脑脊液流动，可严重损害神经功能，导致瘫痪、耳聋和死亡。在NF2中，最严重和危及生命的肿瘤是颅神经神经鞘瘤和颅底脑膜瘤，由于其大小或多发性，无法通过手术治疗。反复切除肿瘤材料可能会使患者出现多种神经功能缺陷，进一步丧失神经功能，并因此虚弱到进一步手术是无济于事的。因此，我们希望找到一种新的药理药物来有效地减少肿瘤的生长，作为手术的替代方案。 NF2主要是由NF2基因产物Merlin的功能障碍引起的，Merlin直接抑制PAK1，PAK1是一种依赖于RAC/CDC42的丝氨酸/苏氨酸激酶。与德国汉堡大学医院(UKE)的Hiroshi Maruta博士合作，我们正在为NF2的小鼠异种移植模型筛选一些PAK1的药理抑制剂。肿瘤是通过将神经鞘瘤细胞系皮下移植到免疫缺陷小鼠的侧翼而形成的。我们的目标是在我们的NF2小鼠模型中找到一种PAK1抑制剂来减少神经鞘瘤的生长。这种药物(S)将对未来产生巨大的临床意义，特别是如果它可以用来取代经常让患者虚弱的侵入性手术。 NCRR BRC用于该项目的资源包括组织培养室、实验室和办公空间。该项目的资金包括日本核因子治愈奖授予S.M.的核因子治疗奖，以及彼得森基金会支持SM研究的赠款。这项工作于2007年6月在犹他州帕克城由儿童肿瘤基金会主办的核因子会议上公布。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder in which patients often develop multiple lesions, including slow growing spinal cord schwannomas and cutaneous schwannomas in the periphery, and meningiomas and gliomas in the brain and spine. Although usually benign and focal schwannomas and meningiomas associated with NF2 can severely compromise neural function leading to paralysis, deafness, and death through compression of critical brain nerves and structures, or blockade of CSF flow. In NF2, the most severe and life-threatening tumors are cranial nerve schwannomas and meningiomas at the skull base, which due to their size or multiplicity, are not surgically accessible. Repeated resection of tumor material can leave patients with multiple neurologic deficits, further loss of nerve function, and so debilitated that further surgery is not helpful. Thus, it is our hope to find a novel pharmacological drug which effectively reduces tumor growth as an alternative to surgery. NF2 is caused primarily by dysfunction of the NF2 gene product called merlin which inhibits directly PAK1, a Rac/ CDC42-dependent Ser/Thr kinase. In collaboration with Dr. Hiroshi Maruta at the Hamburg University Hospital (UKE) in Germany, we are screening a number of pharmacological inhibitors of PAK1 in a murine xenograft model for NF2. Tumors are formed from subcutaneous implantation of a schwannoma cell line into the flanks of immunodeficient mice. It is our objective to find a PAK1 inhibitor which reduces the growth of schwannomas in our NF2 mouse model. This drug(s) will have tremendous clinical implications for the future, particularly if it could be used in place of invasive surgery, which often leaves patients debilitated. The resources of NCRR BRC used for this project include the tissue culture room, laboratory, and office space. Funding for this project include the NF CURE award to S. M. M. from NF CURE JAPAN, and a grant from the Peterson Foundation to support the research of S. M. M. This work was presented at the NF Conference sponsored by the Children's Tumor Foundation in June, 2007 in Park City, Utah.