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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