ATR: a novel therapeutic target for medulloblastoma identified by its role in cerebellar development

ATR：通过其在小脑发育中的作用确定的髓母细胞瘤的新治疗靶点

• 批准号: 8835485
• 负责人: Patrick Yunlong Lang
• 金额: $ 3.34万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-25 至 2019-12-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8835485
• 关键词: ATR gene; Advanced Malignant Neoplasm; Anaphase; Animals; Apoptosis; Apoptotic; Area; Brain; Breeding; Bromodeoxyuridine; Cancer Biology; Cell Cycle; Cell Death; Cell physiology; Cells; Cerebellum; Cessation of life; Child; Childhood Malignant Brain Tumor; Childhood Neurological Disorder; Clinical; Congenital Disorders; Congenital cerebellar hypoplasia; Cytoplasmic Granules; DNA; DNA Damage; DNA biosynthesis; DNA repair protein; Data; Defect; Dependence; Development; Disease; Education; Failure; Fellowship; Flow Cytometry; Genetic; Goals; Growth; Individual; Knock-out; Label; Lead; Life; Malignant neoplasm of brain; Mediating; Mediator of activation protein; Medical; Mitosis; Modeling; Molecular; Mus; Mutation; National Research Service Awards; Neurons; Neurosciences; Pathogenesis; Pathology; Pathway interactions; Pediatric Neoplasm; Pharmacy (field); Phase; Phenotype; Physicians; Plastics; Ploidies; Population; Primary Neoplasm; Process; Proliferating; Protein Deficiency; Regulation; Research Training; Resolution; Role; S Phase; Scientist; Seckel syndrome; Seckel' s Syndrome; Source; Tamoxifen; Testing; Therapeutic; Tissues; Tumor Pathology; United States National Institutes of Health; Work; antitumor effect; cancer therapy; career; caspase-3; caspase-8; cell type; cytochrome c; homologous recombination; in utero; in vivo; malformation; medulloblastoma; neoplastic; neoplastic cell; nerve stem cell; new therapeutic target; novel; novel strategies; postnatal; precursor cell; prenatal; prevent; public health relevance; research study; response; tumor; tumorigenesis

 DESCRIPTION (provided by applicant): My project will investigate the mechanisms underlying cerebellar growth failure and apply this understanding to medulloblastoma, a tumor of excess cerebellar growth. These two interrelated conditions are both important sources of medical illness in children. Cerebellar development depends on the regulated growth of a population of neuronal precursor cells called cerebellar granule neuron progenitors (CGNPs). Failure of these cells to expand their population leads to cerebellar hypoplasia, as seen in the congenital disorder Seckel syndrome. In contrast, excessive proliferation of CGNPs predisposes to medulloblastoma, the most common malignant brain tumor of childhood. Although mutation of the DNA repair protein ATR is known to cause Seckel syndrome, the mechanism through which ATR deficiency results in neurodevelopmental defects is still not fully understood. The hypo-plastic phenotype of Seckel syndrome, however, suggests that ATR disruption may be exploited in the treatment of the hyper-plastic disorder medulloblastoma. The goal of this Kirschstein-NRSA individual fellowship (F30) project is to delineate why ATR is required for cerebellar growth and whether ATR disruption may be used in medulloblastoma treatment. I have found that conditional deletion of ATR in the mouse cerebellum causes widespread DNA damage and cell death in CGNPs, resulting in the formation of small, disorganized cerebella. However, the mechanism by which ATR deficiency leads to CGNP damage and death, and consequently cerebellar hypoplasia, is still unclear. My experiments will use tissues and cells from ATR-deficient mice to reveal where in the cell cycle DNA damage accumulates in CGNPs in response to loss of ATR (Specific Aim 1), and how CGNPs die when they lack ATR (Specific Aim 2). Delineating the mechanism by which CGNPs are damaged and die in response to ATR loss will advance the understanding of Seckel syndrome. CGNP requirement for ATR, as revealed by Seckel syndrome and as seen in ATR-deficient mice, suggests that ATR may be targeted as a novel therapy for medulloblastoma. My preliminary work shows that genetic deletion of ATR during early development in medulloblastoma-prone mice has a profound anti-tumor effect. I thus propose in Specific Aim 3 to determine if deletion of ATR after the point of tumor formation will have a similar anti-tumor effect. My findings will advance cancer treatment by testing the value of targeting ATR in treating medulloblastoma. The proposed training and research plans outlined in this NIH F30 fellowship application will provide me with outstanding education in the areas of cell physiology, neuroscience, cancer biology, and molecular pharmaceutics, and promote my professional development toward a career as a physician-scientist.

 描述（由申请人提供）：我的项目将研究小脑生长障碍的机制，并将这种理解应用于髓母细胞瘤，这是一种小脑过度生长的肿瘤，这两种相互关联的疾病都是儿童小脑发育的重要根源。称为小脑颗粒神经元祖细胞 (CGNP) 的神经前体细胞群体的生长受到调节，这些细胞无法扩大其群体，从而导致小脑。相比之下，CGNP 的过度增殖会导致髓母细胞瘤，这是儿童最常见的恶性脑肿瘤，尽管已知 DNA 修复蛋白 ATR 的突变会导致塞克尔综合征。然而，ATR 缺陷导致的神经发育缺陷尚不完全清楚，但 Seckel 综合征的发育不良表型表明，ATR 破坏可用于治疗增生性疾病。 Kirschstein-NRSA 个人奖学金 (F30) 项目的目标是阐明为什么小脑生长需要 ATR 以及 ATR 破坏是否可用于髓母细胞瘤治疗。 CGNP 中的 DNA 损伤和细胞死亡，导致形成小的、杂乱的小脑。然而，ATR 缺陷导致 CGNP 的机制。损伤和死亡，以及由此导致的小脑发育不全，目前仍不清楚。我的实验将使用 ATR 缺陷小鼠的组织和细胞来揭示细胞周期中 DNA 损伤在 CGNP 中累积的位置，以响应 ATR 的缺失（具体目标 1）。 CGNP 在缺乏 ATR 时如何死亡（具体目标 2）。描述 CGNP 因 ATR 缺失而受损和死亡的机制将促进对 Seckel 综合征的理解。 Seckel 综合征和 ATR 缺陷小鼠所揭示的 CGNP 对 ATR 的要求表明 ATR 可能成为髓母细胞瘤的一种新疗法。因此，我在具体目标 3 中提出，确定在肿瘤形成后删除 ATR 是否会产生类似的抗肿瘤作用，我的发现将通过测试来推进癌症治疗。 NIH F30 奖学金申请中概述的针对 ATR 治疗的价值将为我提供细胞生理学、神经科学、癌症生物学和分子药剂学领域的出色教育，并促进我的专业发展。医生科学家的职业。