Inherited Disorders of Lymphocyte Development

淋巴细胞发育的遗传性疾病

• 批准号: 7994742
• 负责人: Jennifer M. Puck
• 金额: $ 38.24万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7994742
• 关键词: Address; Adoptive Transfer; Antibody Formation; Apoptosis; B cell differentiation; B-Cell Development; B-Lymphocytes; Binding; Blood; Bone Marrow; Candidate Disease Gene; Cell physiology; Cells; Clinical; Coculture Techniques; Cytokine Signaling; Defect; Development; Diagnosis; Disease; Dissection; Enrollment; Etiology; Family member; Gel; Gene Expression; Gene Targeting; Genes; Genotype; Goals; Hematological Disease; Hematopoietic stem cells; Hereditary Disease; Homing; Human; Human Resources; IL7R gene; Immigration; Immune System Diseases; Immunity; Immunologic Deficiency Syndromes; Immunology; Impairment; In Vitro; Inborn Genetic Diseases; Interleukin-4; Interleukin-7; Janus kinase 3; Knockout Mice; Laboratory Finding; Learning; Lymphocyte; Lymphoid; Lymphoid Cell; Malignant Neoplasms; Measures; Modeling; Molecular; Molecular Profiling; Mus; Mutation; Natural Killer Cells; Newborn Infant; Pathogenesis; Pathway interactions; Patients; Peritoneal Fluid; Phenotype; Process; Proteins; RNA Interference; Rare Diseases; Recording of previous events; Role; Sampling; Sequence Analysis; Severe Combined Immunodeficiency; Signal Pathway; Spleen; Stem cells; Surface; System; T-Lymphocyte; TNFRSF5 gene; Testing; Time; Umbilical Cord Blood; Variant; Zinc Fingers; anti-IgM; base; chromatin immunoprecipitation; coronin protein; fitness; human DNA; improved; in vivo; insight; knock-down; lymph nodes; mouse model; novel; peripheral blood; progenitor; programs; public health relevance; receptor; research study; response; transcription factor

DESCRIPTION (provided by applicant): Studies of the molecular basis of human severe combined immunodeficiency (SCID) have ushered in a new era of improved diagnosis and treatment of these rare, but serious genetic disorders and also contributed to the fields of immunology and lymphocyte development. While many disease genes for human SCID are now known, less is known about "leaky" or "partial" SCID, also called combined immunodeficiency (CID); both SCID and CID cases of unknown genotype provide opportunities for further discovery. In addition, the mouse offers the power to dissect lymphoid developmental pathways, and we have discovered a new form of mouse SCID, deficiency of a predicted transcription factor Zbtb1. Mice lacking Zbtb1 have no T cells, but B lineage development is only mildly impaired. This T-B+ SCID model is important because its phenotype resembles that of humans with cytokine signaling pathway defects in the common g chain (gc) receptor, the IL-7 receptor a chain (IL7Ra), and Janus kinase 3 (Jak3), whereas the mouse knockouts lacking these proteins differ from humans in having T cells, but lacking B cells (T-B+). We will combine resources from human patients and mouse models to address the pathogenesis of lymphocyte developmental and functional defects. Samples from patients with SCID/CID will be assessed for defects in known SCID genes, and the cases remaining without a genotype assignment will be studied for defects in new gene candidates. Meanwhile, we will define the specific developmental and functional lymphoid phenotype of Zbtb1 deficient mice to uncover the normal role of Zbtb1 in mouse T and NK cell development and B cell differentiation and function. Comparisons between the Zbtb1- mouse, humans with cytokine signaling defects, and normal human hematopoietic stem cells (HSC) in which ZBTB1 gene expression is knocked down by RNAi will provide new insight into lymphoid development. Thus the goals of this proposal are to (i) assemble samples from SCID and CID patients without known gene defects; (ii) explore SCID pathogenesis of B cell impairment in Zbtb1- mice; (iii) use parallel in vitro and in vivo strategies to compare lymphoid developmental potential of HSC from wild type vs. Zbtb1 knockout mice and normal vs. ZBTB1 knockdown cord blood stem cells; and (iv) find Zbtb1 interacting partners and gene targets, which (along with ZBTB1 itself) will be assessed for mutations that may cause human SCID. PUBLIC HEALTH RELEVANCE: The development of lymphocytes from blood-forming stem cells is incompletely understood, but critically important for treating humans with severe combined immunodeficiency (SCID), other immune and blood diseases, and cancers. We study humans and mice with SCID to find their underlying gene defects and to learn about pathways essential for lymphocyte maturation. We discovered that mice lacking Zbtb1 (a previously unstudied zinc finger protein) cannot form T lymphocytes, though B lymphocytes are present. Zbtb1 is related to transcription factors that repress expression of their target genes. We will investigate how Zbtb1 and its targets function in developing mouse and human lymphoid cells and determine whether defects in Zbtb1 or the genes it acts upon cause human disorders of immunity.

描述（由申请人提供）：对人类严重合并免疫缺陷（SCID）的分子基础的研究已在改善这些罕见但严重遗传疾病的诊断和治疗的新时代，并有助于免疫学和淋巴细胞发展的领域。尽管现在已经知道了许多用于人类SCID的疾病基因，但对“泄漏”或“部分” SCID的了解少，也称为合并的免疫缺陷（CID）。不明基因型的SCID和CID病例都为进一步发现提供了机会。此外，小鼠提供了剖析淋巴发育途径的能力，我们发现了一种新形式的小鼠SCID，缺乏预测的转录因子ZBTB1。缺乏ZBTB1的小鼠没有T细胞，但是B谱系的发展仅受到轻度损害。该T-B+ SCID模型很重要，因为它的表型类似于人类具有细胞因子信号通路缺陷的人类在公共G链（GC）受体，IL-7受体A链（IL7RA）（IL7RA）和Janus激酶3（JAK3）中的表型，而小鼠敲除缺乏这些蛋白质的人群，但缺乏T细胞，但缺乏t细胞（b），但缺乏T细胞（t）。 我们将结合人类患者和小鼠模型的资源，以解决淋巴细胞发育和功能缺陷的发病机理。将评估来自SCID/CID患者的样本，以评估已知SCID基因缺陷的缺陷，并且将研究剩余的没有基因型分配的病例，以解决新基因候选者的缺陷。同时，我们将定义ZBTB1缺乏小鼠的特定发育和功能性淋巴表型，以发现ZBTB1在小鼠T和NK细胞发育以及B细胞分化和功能中的正常作用。 ZBTB1小鼠，具有细胞因子信号缺陷的人与正常的人类造血干细胞（HSC）之间的比较，其中ZBTB1基因表达被RNAi击倒将提供对淋巴样发育的新见解。因此，该提案的目标是（i）从没有已知基因缺陷的SCID和CID患者中组装样本； （ii）探索ZBTB1-小鼠B细胞障碍的SCID发病机理； （iii）使用平行的体外和体内策略比较野生型与ZBTB1基因敲除小鼠的HSC的淋巴发育潜力，以及正常与ZBTB1敲低的脐带血干细胞； （iv）找到ZBTB1相互作用的伴侣和基因靶标，将对可能导致人类SCID的突变进行评估（以及ZBTB1本身）。 公共卫生相关性：从血液形成干细胞的淋巴细胞的发展尚不完全了解，但对于患有严重的免疫缺陷（SCID），其他免疫和血液疾病以及癌症的人类至关重要。我们研究人类和小鼠，以发现其潜在的基因缺陷，并了解淋巴细胞成熟必不可少的途径。我们发现缺乏ZBTB1（以前未研究的锌指蛋白）的小鼠无法形成T淋巴细胞，尽管存在B淋巴细胞。 ZBTB1与抑制其靶基因表达的转录因子有关。我们将研究ZBTB1及其靶标在发育小鼠和人淋巴细胞中的作用，并确定ZBTB1中的缺陷或其作用于引起人类免疫疾病的基因中的缺陷。