Primary Immuno-Deficiencies Affecting Specific Stages of the Immune Response

影响免疫反应特定阶段的原发性免疫缺陷

• 批准号: 8501241
• 负责人: CORNELIS P TERHORST
• 金额: $ 173.37万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-05 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8501241
• 关键词: Affect; Antibody Formation; Area; Autoimmunity; B-Cell Development; B-Lymphocytes; Biochemistry; Boston; Cells; Cellular Immunology; Cellular biology; Clinical Medicine; Common Variable Immunodeficiency; Complement; Complex; DNA ligase IV; Defect; Discipline; Disease; Enzymes; Funding; Genes; Genetic; Homeostasis; Human; Immune; Immune response; Immunoglobulins; Immunology; Individual; Investigation; Israel; Knock-in Mouse; Knowledge; Lead; Malignant Neoplasms; Medical center; Modeling; Molecular; Molecular Immunology; Mus; Mutate; Mutation; Natural Immunity; Natural Killer Cells; Outcome; Pathogenesis; Patients; Pediatric Hospitals; Program Research Project Grants; Protein Chemistry; Proteins; Receptor Signaling; Research Personnel; Role; Scientist; Severe Combined Immunodeficiency; Signaling Molecule; Staging; Surface; Syndrome; T-Lymphocyte; Technology; Therapeutic; X-Linked lymphoproliferative disorders; congenital immunodeficiency; insight; macrophage; mouse model; neutrophil; programs; research study; response; transcription factor

This revised application for our new Program Project Grant brings together a group of investigators who are experts in the areas of molecular and cellular immunology and human and mouse genetics. We propose to study the role of single genes in the pathogenesis of X-linked Lymphoproliferative syndrome (XLP), Common variable immunodeficiency (CVID), Omenn syndrome and Severe Combined Immunodeficiencies (SCID) in an application, entitled: "Primary Immunodeficiencies Affecting Specific Stages of the Adaptive Immune Rresponse" Because of successful preliminary analyses of patient materials, exciting findings in genetically altered mice, this application seeks to define how mutations in the SH2D1A, SH2D1B/C, TACI, RAG-1/2, DNA Ligase IV or Cernunnos genes affect T and B cell development and T cell dependent and/or T cell-independent immunoglobulin responses. We will use our recently acquired insights into the causes of these diseases in the following four interlinked projects and an Administrative Core: Project #1 Role of the SAP (SH2D1A) gene in T cell-dependent antibody responses. Cox Terhorst, Beth Israel Deaconess Medical Center. Project #2 Role of in TACI mutations in Common Variable Immunodeficiency Raif Geha, Children's Hospital of Boston. Project #3 Gene knock-in models for Omenn syndrome and leaky SCID. Luigi Notarangelo, Children's Hospital of Boston. Project #4 Mouse Models of Severe Combined Immunodeficiencies. Fred Alt, Children's Hospital of Boston. Core A Administrative Core Cox Terhorst, Beth Israel Deaconess Medical Center. The outcomes of proposed studies should lead to better understanding of the complex and often alternate disease manifestations that are caused by mutations in a single gene. The results of these studies should suggest therapeutic strategies that can be applied to these PID patients and may unravel molecular and cellular mechanisms that are generally involved in immune dysregulation, autoimmunity and cancer.

我们的新计划项目补助金的修订申请汇集了一组研究人员，他们是 分子和细胞免疫学以及人类和小鼠遗传学领域的专家。我们建议 研究单基因在X连锁恶性增殖综合征（XLP）发病机制中的作用， 变异性免疫缺陷（CVID）、Omenn综合征和严重联合免疫缺陷（SCID）， 一项申请，题为： “影响适应性免疫反应特定阶段的原发性免疫缺陷” 由于对患者材料的初步分析成功，在转基因小鼠中的令人兴奋的发现， 本申请试图定义SH 2D 1A、SH 2D 1B/C、TACI、RAG-1/2、DNA连接酶IV 或Cernunnos基因影响T和B细胞发育以及T细胞依赖性和/或T细胞非依赖性 免疫球蛋白反应。我们将利用我们最近对这些疾病的原因的了解， 以下四个相互关联的项目和一个行政核心： 项目#1 SAP（SH 2D 1A）基因在T细胞依赖性抗体应答中的作用。 考克斯特霍斯特，贝斯以色列女执事医疗中心。 项目#2 TACI突变在常见变异型免疫缺陷中的作用 Raif Geha波士顿儿童医院 项目#3 Omenn综合征和渗漏性SCID的基因敲入模型。 路易吉·诺塔朗吉洛波士顿儿童医院 项目#4严重联合免疫缺陷的小鼠模型。 弗雷德·阿尔特波士顿儿童医院 核心A行政核心 考克斯特霍斯特，贝斯以色列女执事医疗中心。 拟议研究的结果应有助于更好地了解复杂和经常交替的 由单个基因突变引起的疾病表现。这些研究的结果应该 提出了可应用于这些PID患者的治疗策略， 这些细胞机制通常涉及免疫失调、自身免疫和癌症。

项目成果

Functional overlaps between XLF and the ATM-dependent DNA double strand break response.

• DOI: 10.1016/j.dnarep.2014.01.010
• 发表时间: 2014-04
• 期刊: DNA REPAIR
• 影响因子: 3.8
• 作者: Kumar, Vipul;Alt, Frederick W.;Oksenych, Valentyn
• 通讯作者: Oksenych, Valentyn

Immune deficiency caused by impaired expression of nuclear factor-kappaB essential modifier (NEMO) because of a mutation in the 5' untranslated region of the NEMO gene.

由于 NEMO 基因 5 非翻译区突变，核因子 kappaB 必需修饰物 (NEMO) 表达受损而导致免疫缺陷。

• DOI: 10.1016/j.jaci.2010.04.026
• 发表时间: 2010
• 期刊: The Journal of allergy and clinical immunology
• 作者: Mooster,JanaL;Cancrini,Caterina;Simonetti,Alessandra;Rossi,Paolo;DiMatteo,Gigliola;Romiti,MariaLuisa;DiCesare,Silvia;Notarangelo,Luigi;Geha,RaifS;McDonald,DouglasR
• 通讯作者: McDonald,DouglasR

Heterozygosity for transmembrane activator and calcium modulator ligand interactor A144E causes haploinsufficiency and pneumococcal susceptibility in mice.

• DOI: 10.1016/j.jaci.2016.07.028
• 发表时间: 2017-04
• 期刊: The Journal of allergy and clinical immunology
• 作者: Jabara HH;Lee JJ;Janssen E;Ullas S;Liadaki K;Garibyan L;Benson H;Sannikova T;Bram R;Hammarstrom L;Cruz AC;Siegel R;Manis J;Malley R;Geha RS
• 通讯作者: Geha RS

Whole-exome sequencing identifies tetratricopeptide repeat domain 7A (TTC7A) mutations for combined immunodeficiency with intestinal atresias.

• DOI: 10.1016/j.jaci.2013.06.013
• 发表时间: 2013-09
• 期刊: The Journal of allergy and clinical immunology
• 作者: Chen R;Giliani S;Lanzi G;Mias GI;Lonardi S;Dobbs K;Manis J;Im H;Gallagher JE;Phanstiel DH;Euskirchen G;Lacroute P;Bettinger K;Moratto D;Weinacht K;Montin D;Gallo E;Mangili G;Porta F;Notarangelo LD;Pedretti S;Al-Herz W;Alfahdli W;Comeau AM;Traister RS;Pai SY;Carella G;Facchetti F;Nadeau KC;Snyder M;Notarangelo LD
• 通讯作者: Notarangelo LD

LPS-responsive beige-like anchor (LRBA) gene mutation in a family with inflammatory bowel disease and combined immunodeficiency.

• DOI: 10.1016/j.jaci.2012.05.043
• 发表时间: 2012-08
• 期刊: JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
• 影响因子: 14.2
• 作者: Alangari, Abdullah;Alsultan, Abdulrahman;Adly, Nouran;Massaad, Michel J.;Kiani, Iram Shakir;Aljebreen, Abdulrahman;Raddaoui, Emad;Almomen, Abdul-Kareem;Al-Muhsen, Saleh;Geha, Raif S.;Alkuraya, Fowzan S.
• 通讯作者: Alkuraya, Fowzan S.