Myeloablative conditioning and late complications in ARTEMIS-deficient SCID

ARTEMIS 缺陷 SCID 的清髓调理和晚期并发症

基本信息

批准号：
9251366
负责人：
JoAnn Sekiguchi
金额：
$ 23.25万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-20 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9251366
关键词：
Adaptive Immune System Alkylating Agents Alleles Antigen Receptors Antigens Area Autoimmunity B-Lymphocytes Bone Marrow Transplantation Busulfan Cell physiology Cells Chemotherapy-Oncologic Procedure Clinical Code Cyclophosphamide DNA Double Strand Break DNA Repair DNA Repair Gene DNA lesion DNA-PKcs Defect Dental Development Disease Double Strand Break Repair Endocrine Engraftment Exhibits Failure Gene Mutation Gene Rearrangement Genes Goals Growth Hematopoietic Stem Cell Transplantation Human Hypersensitivity Immune Immunologic Deficiency Syndromes Immunologics Impairment Individual Inherited Investigation Ionizing radiation J segment gene LIG4 gene Late Effects Lead Lymphocyte Lymphoid Malignant Neoplasms Mature B-Lymphocyte Monoclonal Antibodies Morbidity - disease rate Mutate Mutation Myeloablative Chemotherapy Natural Killer Cells Nonhomologous DNA End Joining Organ Pathway interactions Patients Phenotype Play Predisposition Process Proteins Proto-Oncogene Protein c-kit Radiation Radiation Tolerance Receptor Gene Regimen Reporting Research Role Severe Combined Immunodeficiency Severities T-Lymphocyte Time Tissues Toxic effect Transplantation Conditioning V(D)J Recombination artemis cell type chemotherapy conditioning congenital immunodeficiency curative treatments cytotoxic cytotoxicity effective therapy endonuclease hematopoietic cell transplantation improved insight irradiation mortality mouse model mutant null mutation prevent radiosensitive receptor reconstitution repaired response success tumorigenesis

项目摘要

PROJECT ABSTRACT The vastly diverse antigen receptor genes are assembled from numerous V, D and J coding segments via the lymphoid specific DNA rearrangement, V(D)J recombination. Defective V(D)J recombination impairs lymphocyte development and thus, results in immunodeficiency. The non-homologous end joining (NHEJ) pathway is required during V(D)J recombination by virtue of its role as one of the major DNA double strand break (DSB) repair pathways. Mutations in nearly all of the NHEJ genes have been found in association with human primary immunodeficiency syndromes. ARTEMIS is the most frequently mutated NHEJ gene and was initially discovered in the radiation sensitive severe combined immunodeficiency syndrome, RS-SCID. NHEJ- deficient patients can undergo hematopoietic cell transplantation to reconstitute T and B cell functions. However, because NHEJ is critical for DSB repair in all cell types, conditioning regimens involving radiation cause excessive tissue damage and can lead to mortality. ARTEMIS-deficient patients have been successfully engrafted with T and B cells with myeloablative conditioning using alkylating agents. However, these patients exhibit late complications including growth failure, endocrine deficiencies and dental abnormalities. The goals of this proposal are to elucidate the mechanisms underlying the toxicities associated with myeloablative conditioning with alkylating agents using our previously developed and characterized mouse models of NHEJ- deficient SCID and to determine the efficacy of alternative conditioning regimens. The potential for late onset tumorigenesis associated will also be examined. Together, these studies will provide mechanistic insight into the causes of late toxicities in NHEJ-deficient primary immunodeficiencies and potentially lead to the development of more effective therapies.

项目摘要多种多样的抗原受体基因由众多 V、D 和 J 编码片段组装而成通过淋巴特异性 DNA 重排、V(D)J 重组。有缺陷的 V(D)J 重组损害淋巴细胞发育，从而导致免疫缺陷。非同源末端连接（NHEJ） V(D)J 重组过程中需要途径，因为它是主要 DNA 双链之一破坏（DSB）修复途径。几乎所有 NHEJ 基因的突变都被发现与以下疾病相关：人类原发性免疫缺陷综合征。 ARTEMIS 是最常突变的 NHEJ 基因，最初发现于辐射敏感的严重联合免疫缺陷综合征，RS-SCID。 NHEJ- 缺陷患者可以接受造血细胞移植来重建T和B细胞功能。然而，由于 NHEJ 对于所有细胞类型的 DSB 修复都至关重要，因此涉及放射治疗的预处理方案造成过度的组织损伤并可能导致死亡。 ARTEMIS 缺陷患者已成功使用烷化剂进行清髓性调节后植入 T 和 B 细胞。然而，这些患者表现出晚期并发症，包括生长障碍、内分泌缺陷和牙齿异常。目标该提案的目的是阐明与清髓性药物相关的毒性的潜在机制使用我们之前开发和表征的 NHEJ- 小鼠模型，用烷化剂进行调理 SCID 缺陷并确定替代调理方案的功效。迟发的可能性还将检查相关的肿瘤发生。这些研究将共同提供机制方面的见解 NHEJ 缺陷型原发性免疫缺陷患者晚期毒性的原因，并可能导致开发更有效的疗法。