Role of Cited2 in lens development and hyaloid vascular regression

Cited2 在晶状体发育和玻璃体血管退化中的作用

• 批准号: 7895531
• 负责人: YU-CHUNG YANG
• 金额: $ 23.48万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7895531
• 关键词: Address; Adult; Apoptosis; Area; Biological; Blood Vessels; Congenital Heart Defects; Crystalline Lens; D-Aspartic Acid; Defect; Development; Disease; Disease model; EP300 gene; Embryo; Epithelial Cells; Exhibits; Eye; Eye Abnormalities; Eye Development; Eye diseases; Family; Figs - dietary; Genetic; Glutamic Acid; Homeostasis; Hyperplasia; Hypoxia; Knock-out; Knockout Mice; Knowledge; Laboratories; Mediating; Modeling; Mus; Oncogenes; Organ; Oxygen; Peptides; Pilot Projects; Play; Pregnancy; Principal Investigator; Research; Retina; Role; Serum; Signal Transduction; Stimulus; Systemic disease; Tail; Testing; Therapeutic; Tissues; Trans-Activators; Vascular Endothelial Growth Factors; Vascular System; adenovirus mediated delivery; chetomin; cytokine; in vivo; inhibitor/antagonist; lens; lens morphogenesis; loss of function; member; mouse model; novel; null mutation; overexpression; public health relevance; response; vessel regression

DESCRIPTION (provided by applicant): Cited2 (CBP/p300-interacting transactivators with glutamic acid (E) and aspartic acid (D)-rich tail 2) is a founding member of a new family of transcriptional modulators. My laboratory cloned Cited2 and showed that Cited2 is induced by many biological stimuli including cytokines, serum and LPS. It is widely expressed and is a transforming gene when overexpressed. In order to address the role of Cited2 in vivo, we generated mice with a null mutation at the Cited2 locus and found that deletion of Cited2 causes Cited2-/- embryos to die at mid- to late gestation with several developmental defects. Cited2 expression is detectable in the developing lens. Histological examination of Cited2-/- embryos revealed persistent lens stalk, a smaller lens and hyaloid hypercellularity consisting of aberrant vasculature in the eye. The latter is similar to the pathological features of PHPV (Persistent hyperplastic primary vitreous), a congenital eye disorder leading to abnormal lenticular development and secondary changes of the retina and the eye. Tissue specific deletion of Cited2 in the lens also resulted in lens stalk formation, a smaller lens and failed regression of hyaloid vascular system (HVS) in adult eyes. These results suggest that they are primary defects associated with loss of Cited2 expression in the lens and that Cited2 is involved in lens morphogenesis and hyaloid vascular formation/regression during development. Cited2 is a negative modulator for HIF-1 function and loss of Cited2 may result in upregulated HIF-1 mediated hypoxic responses. This mechanism is partially responsible for the heart defects observed in Cited2 null embryos. Lens-specific deletion of HIF-1 eliminates the aberrant hyaloid hypercellularity in Cited2 deficient embryos, suggesting that dysregulated HIF-1 signaling may play a role in aberrant HVS formation in Cited2-/- eyes. Although it is known that lens is a hypoxic organ and HIF-1 is highly expressed in the lens epithelial cells, a direct and detailed examination of the hypoxia level of a developing mouse lens and the consequences of its deregulation has never been performed. This pilot study, which is a new research area for the principal investigator, attempts generate compound mice with deletions of Cited2 and HIF-1 or VEGF to explore the hypothesis that a Cited2-HIF-1 genetic interaction is essential for HVS formation and regression. Since lens- specific Cited2 knockout mouse exhibits failed HVS regression and deletion of HIF-1 rescues the abnormal hyaloid vasculature in Cited2 knockout eyes, lens-specific Cited2 knockout mice could not only be used as a novel disease model for PHPV but also for testing potential HIF-1 inhibitors. PUBLIC HEALTH RELEVANCE: The accomplishment of the proposed study will not only advance our knowledge in the lens development and the influence of hypoxia on the formation and regression of hyaloid vascular system but also provide potential therapeutic principles in treating eye disorders and other systemic diseases with dysregulated HIF-1 signaling.

描述（由申请人提供）：引用2（CBP/P300相互作用谷氨酸（E）和天冬氨酸（D）-Rich Tail 2）是新的转录调节剂家族的创始成员。我的实验室克隆引用了2，并表明引用2是由包括细胞因子，血清和LP在内的许多生物刺激诱导的。它被广泛表达，是过表达时转化基因的。为了解决体内引用2的作用，我们在cuted2基因座上产生了无效突变的小鼠，发现cusited2引起的删除引用了2-/ - 胚胎在妊娠中期至晚期死亡，并有几个发育缺陷。在发育中的晶状体中可以检测到引用2的表达。引用的2-/ - 胚胎的组织学检查显示，持续的晶状体茎，较小的晶状体和透明的超细胞性，由眼睛中异常的脉管系统组成。后者类似于PHPV（持续增生原代玻璃体）的病理特征，这是一种先天性眼部疾病，导致异常的胸部发育和视网膜和眼睛的次要变化。晶状体中引用2的组织特异性缺失也导致晶状体茎的形成，较小的晶状体和成年眼睛中透镜血管系统（HVS）的失败。这些结果表明，它们是与晶状体中cusit2表达丧失相关的主要缺陷，并且引用2参与了发育过程中晶状体形态发生和透镜血管形成/回归。 CITED2是用于HIF-1功能的负调节剂，Cusited2的丢失可能会导致HIF-1介导的低氧反应。该机制部分原因是在引用2个null胚胎中观察到的心脏缺陷。 HIF-1的透镜特异性缺失消除了引用2缺陷胚胎中异常的透明透明性高细胞性，这表明HIF-1信号失调可能在CITED2 - / - 眼中的异常HVS形成中起作用。尽管众所周知，晶状体是一种缺氧器官，HIF-1在晶状体上皮细胞中高度表达，但直接和详细的检查了发育中的小鼠晶状体的缺氧水平及其放松管制的后果从未进行过。这项试验研究是主要研究人员的新研究领域，尝试生成具有删除Cited2和HIF-1或VEGF的复合小鼠，以探讨以下假设：cuped2-HIF-1遗传相互作用对于HVS形成和回归至关重要。由于特异性引用的2基因敲除小鼠表现出失败的HVS回归，而HIF-1的缺失挽救了引用的2敲除眼中异常的透明透明脉管系统，因此镜头特异性引用2基因敲除小鼠不仅可以用作PHPV的新型疾病模型，而且可以测试潜在的HIF-1抑制剂。公共卫生相关性：拟议研究的完成不仅将提高我们在晶状体发展方面的知识，以及缺氧对透明血管系统的形成和回归的影响，而且还为治疗眼部疾病和其他系统性疾病的HIF-1信号传导提供了潜在的治疗原理。

项目成果

Deletion of HIF-1ýý partially rescues the abnormal hyaloid vascular system in Cited2 conditional knockout mouse eyes.

在 Cited2 条件性基因敲除小鼠眼中，HIF-1××的缺失可以部分挽救异常的玻璃体血管系统。

• 发表时间: 2012
• 期刊: Molecular vision
• 影响因子: 2.2
• 作者: Huang,Tai-Qin;Wang,Yiwei;Ebrahem,Quteba;Chen,Yu;Cheng,Cindy;Doughman,YongQiu;Watanabe,Michiko;Dunwoodie,SallyL;Yang,Yu-Chung
• 通讯作者: Yang,Yu-Chung