Inherited Disorders of Lymphocyte Development

描述（由申请人提供）：对人类严重联合免疫缺陷（SCID）的分子基础的研究开创了一个新时代，可以改善这些罕见但严重的遗传性疾病的诊断和治疗，并有助于免疫学和淋巴细胞发育领域。虽然现在已知许多人类SCID的疾病基因，但对“泄漏”或“部分”SCID（也称为联合免疫缺陷（CID））知之甚少;未知基因型的SCID和CID病例都为进一步发现提供了机会。此外，小鼠提供了解剖淋巴发育途径的能力，我们已经发现了一种新形式的小鼠SCID，缺乏预测的转录因子Zbtb 1。缺乏Zbtb 1的小鼠没有T细胞，但B谱系发育仅轻度受损。该T-B+ SCID模型是重要的，因为其表型类似于在共同g链（gc）受体、IL-7受体a链（IL 7 Ra）和Janus激酶3（Jak 3）中具有细胞因子信号传导途径缺陷的人的表型，而缺乏这些蛋白质的小鼠敲除与人的不同之处在于具有T细胞，但缺乏B细胞（T-B+）。 我们将联合收割机从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制。将评估来自SCID/CID患者的样本中已知SCID基因的缺陷，并将研究剩余的没有基因型分配的病例中新候选基因的缺陷。同时，我们将确定Zbtb 1缺陷小鼠的特定发育和功能淋巴表型，以揭示Zbtb 1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。Zbtb 1-小鼠、细胞因子信号传导缺陷的人类和ZBTB 1基因表达被RNAi敲低的正常人类造血干细胞（HSC）之间的比较将为淋巴发育提供新的见解。因此，该提议的目标是（i）收集来自没有已知基因缺陷的SCID和CID患者的样品;（ii）探索Zbtb 1-小鼠中B细胞损伤的SCID发病机理;（iii）使用平行的体外和体内策略来比较来自野生型与Zbtb 1敲除小鼠和正常与ZBTB 1敲减脐带血干细胞的HSC的淋巴发育潜力;和（iv）发现Zbtb 1相互作用配偶体和基因靶，其（沿着ZBTB 1本身）将被评估可能引起人SCID的突变。

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.