Detecting invading glioma cells through in vivo molecular imaging of the cell sur

通过细胞表面的体内分子成像检测入侵的神经胶质瘤细胞

基本信息

批准号：
7562871
负责人：
SUSANN M BRADY-KALNAY
金额：
$ 40万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7562871
关键词：
Adult Affinity Binding Biological Assay Brain Brain Neoplasms Cell Adhesion Molecules Cell Surface Receptors Cells Characteristics Cleaved cell Clinical Collaborations Contrast Media Data Detection Development Diagnosis Diagnostic Disease Down-Regulation Effectiveness Excision Exhibits Fluorescence Glioblastoma Glioma Histocytochemistry Hour Human Image Imaging Techniques Imaging technology Immigration Injection of therapeutic agent Intracranial Neoplasms Invaded Label Lead Life Magnetic Resonance Imaging Measures Modeling Molecular Molecular Target Monitor Neuraxis Neuroglia Neurosurgeon Operative Surgical Procedures Patients Peptides Primary Brain Neoplasms Property Proteins Proteolysis Proteolytic Processing Rodent Sampling Site Slice System Tail Testing Therapeutic Therapeutic Agents Time Tissues Veins cohort glioma cell line human PTPRT protein imaging probe in vivo molecular imaging neoplastic cell neurosurgery novel strategies outcome forecast public health relevance reconstruction research study tumor

项目摘要

DESCRIPTION (provided by applicant): We identified a unique marker of invading glioma cells that arises from PTP5 cleavage. We developed a specific molecular imaging probe that binds to the cleaved PTP5 fragment and recognizes glioblastomas. Therefore, we will test the hypothesis that this probe marks high-grade human gliomas and defines the invading tumor margin. We will explore its utility as a diagnostic molecular imaging agent and as a therapeutic. Primary brain tumors commonly arise from supporting glial cells within the central nervous system. These tumors are called gliomas and typically disperse widely throughout the brain making complete surgical resection impossible. The invasive properties of gliomas lead to difficulties in determining the extent of invasion and make this disease virtually incurable with a mean survival of approximately one year. PTP5 is a cell surface receptor protein tyrosine phosphatase (RPTP) and a cell adhesion molecule whose expression is down-regulated in human gliomas. Very recent data suggests that during PTP5 down-regulation, the protein is proteolyzed and a small fragment remains associated with the glioblastoma cells. Here we describe studies that utilize a unique robust molecular imaging probe for the PTP5 fragment and test its effectiveness in vivo. Our hypothesis is that the probe will detect the migrating and invading glioblastomas at the cellular level and can eventually be used in human patients to image the tumors with magnetic resonance imaging (MRI). Identification of key molecular targets such as PTP5 will allow development of novel strategies to diagnose, image and eventually treat gliomas. It is envisioned that this probe could also be utilized during surgery to guide neurosurgery of the tumors enabling more complete and precise tumor resection, which will enhance patient survival. Aim 1: Determine the extent of association of the cleaved fragment of PTP5 with invasiveness of human gliomas of various types and grades. Aim 2: Assess the utility of peptide probes to monitor migrating glioma cells in an ex vivo brain slice invasion assay. Aim 3: Examine the utility of the probe to detect tumors and migrating glioma cells in vivo in heterotopic and orthotopic human brain tumor models in rodents. Public Health Relevance: We identified a unique marker of invading glioma cells that can be molecularly imaged in vivo. We propose to further characterize this unique marker and to explore its utility as both a diagnostic molecular imaging agent and a therapeutic. We hypothesize that the probe will detect the migrating and invading glioblastomas at the cellular level, therefore, the probe can be used in human patients to image invasive gliomas with magnetic resonance imaging (MRI).

描述（由申请人提供）：我们鉴定了一种由 PTP5 裂解产生的入侵神经胶质瘤细胞的独特标记。我们开发了一种特定的分子成像探针，可以与切割的 PTP5 片段结合并识别胶质母细胞瘤。因此，我们将检验该探针标记高级别人类神经胶质瘤并定义侵入肿瘤边缘的假设。我们将探索其作为诊断分子成像剂和治疗剂的用途。原发性脑肿瘤通常由中枢神经系统内的支持神经胶质细胞引起。这些肿瘤被称为神经胶质瘤，通常广泛分散在整个大脑中，使得完全手术切除是不可能的。神经胶质瘤的侵袭特性导致难以确定侵袭程度，并使这种疾病几乎无法治愈，平均生存期约为一年。 PTP5 是一种细胞表面受体蛋白酪氨酸磷酸酶 (RPTP) 和一种细胞粘附分子，其表达在人胶质瘤中下调。最近的数据表明，在 PTP5 下调期间，该蛋白质被蛋白水解，并且一小片段仍然与胶质母细胞瘤细胞相关。在这里，我们描述了利用独特的稳健分子成像探针检测 PTP5 片段并测试其体内有效性的研究。我们的假设是，该探针将在细胞水平上检测迁移和侵袭的胶质母细胞瘤，并最终可用于人类患者，通过磁共振成像（MRI）对肿瘤进行成像。 PTP5 等关键分子靶点的识别将有助于开发新的策略来诊断、成像并最终治疗神经胶质瘤。预计该探针还可以在手术期间用于指导肿瘤的神经外科手术，从而实现更完整和更精确的肿瘤切除，这将提高患者的生存率。目标 1：确定 PTP5 切割片段与各种类型和级别的人类神经胶质瘤侵袭性的关联程度。目标 2：评估肽探针在离体脑切片侵袭测定中监测迁移神经胶质瘤细胞的效用。目标 3：检查探针在啮齿动物异位和原位人脑肿瘤模型中体内检测肿瘤和迁移神经胶质瘤细胞的实用性。公共健康相关性：我们发现了一种可以在体内进行分子成像的入侵神经胶质瘤细胞的独特标记。我们建议进一步表征这种独特的标记物，并探索其作为诊断分子成像剂和治疗剂的效用。我们假设该探针将在细胞水平上检测迁移和侵袭性胶质母细胞瘤，因此，该探针可用于人类患者，通过磁共振成像（MRI）对侵袭性胶质瘤进行成像。