Long noncoding RNAs and their contribution to 22q11.2 deletion syndrome

长非编码 RNA 及其对 22q11.2 缺失综合征的贡献

• 批准号: 9089900
• 负责人: NICOLAI Stanislas Cyrille VAN OERS
• 金额: $ 43.15万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9089900
• 关键词: 22q11.2; Address; Adult; Autoimmune Diseases; Birth; Calcium; Cardiac; Cell Count; Cell physiology; Cellularity; Chromosomes; Clinical; Complex; Defect; Development; Developmental Delay Disorders; DiGeorge Syndrome; Diagnosis; Disease; Dysmorphology; Effectiveness; Embryonic Development; Epithelial; Face; Flow Cytometry; Genes; Growth; Growth and Development function; Health; Heart; Heart Abnormalities; Histology; Homologous Gene; Human; Hypocalcemia result; Hypoparathyroidism; Immunohistochemistry; Individual; Infection; Knock-out; Knockout Mice; Learning Disorders; Link; Lymphopenia; MicroRNAs; Molecular; Mus; Natural regeneration; Newborn Infant; Online Mendelian Inheritance In Man; Output; Parathyroid gland; Pathway interactions; Patients; Peripheral; Pharyngeal Apparatus; Phenotype; RNA; Recovery; Regulatory T-Lymphocyte; Reporting; Reverse Transcriptase Polymerase Chain Reaction; Role; Schizophrenia; Severities; Staging; Stress; Syndrome; T-Cell Development; T-Lymphocyte; Thymic Tissue; Thymic epithelial cell; Thymus Gland; Tissues; Triad Acrylic Resin; Untranslated RNA; adaptive immunity; base; clinical phenotype; comparative; conotruncal anomaly face syndrome; defined contribution; microdeletion; novel; regenerative; response; thymic hypoplasia; tissue repair; transcriptome; transcriptome sequencing

 DESCRIPTION (provided by applicant): 22q11.2 deletion syndrome is one of the most common microdeletion syndromes in humans. The deletions result in a haploinsufficiency of over 60 genes, 4 microRNAs, and a group of uncharacterized long noncoding RNAs. Individuals with 22q11.2 deletion syndrome can present with many clinical complications including three that are commonly linked, thymic hypoplasia, hypocalcemia related to the parathyroid hypoplasia, and cardiac anomalies. Additional clinical manifestations include growth delay, facial dysmorphology, learning disorders, and/or schizophrenia. Those patients with a hypoplastic thymus have reduced thymopoiesis. This causes a peripheral T cell lymphopenia, with fewer effector and regulatory T cells present in these individuals. Insufficient numbers of such T cells increases the severity and duration of infections and autoimmune disorders. The thymus hypoplasia, the hypoparathyroidism, and defects in the outflow tracts of the heart, result from impaired tissue specification of the pharyngeal apparatus. We characterized human thymic tissues from normal and 22q11.2 deletion syndrome patients with a combination of histology, immunohistochemistry, flow cytometry, microRNA (miR) arrays, RT-PCR, and RNA sequencing. Preliminary findings reveal a deficiency of miR-205 and the surrounding long noncoding RNA (lncRNA, MIR205HG) in the hypoplastic tissues from a subset of 22q11.2 deletion syndrome patients. We have generated conditional knockout mice for the murine homolog of the lncRNA and have miR-205 conditional knockout lines. Preliminary findings indicate that miR-205 is required for T cell output during normal and stress situations. A complete deficiency of lncRNA results in a growth delay in the mice. By using diverse conditional knockout mice, and comparing the phenotypes in these mice to those reported for chromosome 22q11.2 deletion syndrome, we will determine how the novel RNA species result in poor T cell output and developmental delays. The studies will include a comparative analysis of human thymii from normal and 22q11.2 deletion syndrome patients.

 描述（由申请人提供）：22q11.2缺失综合征是人类最常见的微缺失综合征之一。这些缺失导致 60 多个基因、4 个 microRNA 和一组未表征的长非编码 RNA 的单倍体不足。患有 22q11.2 缺失综合征的个体可能会出现许多临床并发症，包括三种常见的并发症：胸腺发育不全、与甲状旁腺发育不全相关的低钙血症和心脏异常。其他临床表现包括生长迟缓、面部畸形、学习障碍和/或精神分裂症。那些胸腺发育不全的患者胸腺生成能力降低。这会导致外周 T 细胞淋巴细胞减少，这些个体中存在较少的效应 T 细胞和调节性 T 细胞。此类 T 细胞数量不足会增加感染和自身免疫性疾病的严重程度和持续时间。胸腺发育不全、甲状旁腺功能减退和心脏流出道缺陷是由咽部组织规格受损造成的。我们结合组织学、免疫组织化学、流式细胞术、microRNA (miR) 阵列、RT-PCR 和 RNA 测序，对正常和 22q11.2 缺失综合征患者的人类胸腺组织进行了表征。初步研究结果显示，22q11.2 缺失综合征患者的发育不全组织中存在 miR-205 和周围的长非编码 RNA（lncRNA、MIR205HG）缺陷。我们已经生成了 lncRNA 小鼠同源物的条件敲除小鼠，并拥有 miR-205 条件敲除系。初步研究结果表明，在正常和应激情况下，T 细胞输出需要 miR-205。 lncRNA完全缺乏会导致小鼠生长迟缓。通过使用不同的条件敲除小鼠，并将这些小鼠的表型与报道的染色体 22q11.2 缺失综合征的表型进行比较，我们将确定新型 RNA 物种如何导致 T 细胞输出不良和发育迟缓。这些研究将包括对正常人和 22q11.2 缺失综合征患者的人类胸腺进行比较分析。