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: 7666002
• 负责人: YU-CHUNG YANG
• 金额: $ 19.63万
• 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 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7666002
• 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）：Cited2 (CBP/p300-与谷氨酸（E)和天冬氨酸(D)-富尾2相互作用的transactivators）是一个新的转录调节剂家族的创始成员。我的实验室克隆了Cited2，发现Cited2可被多种生物刺激诱导，包括细胞因子、血清和LPS。它广泛表达，当过度表达时是一个转化基因。为了研究Cited2在体内的作用，我们在小鼠中产生了Cited2位点的零突变，发现Cited2的缺失会导致Cited2-/-胚胎在妊娠中后期死亡，并伴有几种发育缺陷。在发育中的晶状体中可检测到Cited2的表达。Cited2-/-胚胎的组织学检查显示晶状体柄持久，晶状体较小，眼内透明体细胞增多，血管异常。后者与PHPV（持续性原发性玻璃体增生）的病理特征相似，PHPV是一种先天性眼部疾病，导致晶状体发育异常和视网膜和眼睛的继发性改变。晶状体中Cited2的组织特异性缺失也导致成人眼晶状体柄形成、晶状体变小和玻璃体血管系统（HVS）退化失败。这些结果表明，它们是与晶状体中Cited2表达缺失相关的主要缺陷，并且在发育过程中，Cited2参与晶状体形态发生和玻璃体血管形成/退化。Cited2是HIF-1功能的负调节因子，Cited2的缺失可能导致HIF-1介导的缺氧反应上调。这一机制部分解释了在Cited2缺失胚胎中观察到的心脏缺陷。HIF-1的晶状体特异性缺失消除了Cited2缺陷胚胎中异常的透明体高细胞性，这表明失调的HIF-1信号可能在Cited2-/-眼睛中异常的HVS形成中起作用。虽然已知晶状体是一个缺氧器官，HIF-1在晶状体上皮细胞中高度表达，但对发育中的小鼠晶状体的缺氧水平及其解除管制的后果进行直接和详细的检查从未进行过。这项先导研究是首席研究员的一个新的研究领域，试图产生Cited2和HIF-1或VEGF缺失的复合小鼠，以探索Cited2-HIF-1基因相互作用对HVS的形成和消退至关重要的假设。由于晶状体特异性的Cited2基因敲除小鼠表现出HVS消退失败，而HIF-1的缺失挽救了Cited2基因敲除眼睛中异常的玻璃体血管，因此晶状体特异性的Cited2基因敲除小鼠不仅可以作为PHPV的新型疾病模型，还可以用于测试潜在的HIF-1抑制剂。公共卫生相关性：该研究的完成不仅将提高我们对晶状体发育和缺氧对玻璃体血管系统形成和退化的影响的认识，而且还将为治疗眼部疾病和其他HIF-1信号失调的全体性疾病提供潜在的治疗原则。