Physiological significance of cellular translocation of the intestine-specific homeodomain protein Cdx2

肠道特异性同源域蛋白 Cdx2 细胞易位的生理意义

• 批准号: nhmrc : 164803
• 负责人: A/Pr Joan Heath
• 金额: $ 13.1万
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2001
• 资助国家: 澳大利亚
• 起止时间: 2001-01-01 至 2003-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/physiological-significance-cellular-protein-cdx2/80861
• 关键词: Physiological; significance; cellular; translocation; intestine

Ulcerative colitis and Crohn's disease are debilitating inflammatory diseases of the bowel. Conservative estimates (Australian Crohn's and Colitis Association) suggest that at least 23,000 Australians are affected (>1 in 1000). Ten years after onset, there is an estimated risk of 0.5-1.0% per year of pancolitis patients developing full-blown bowel cancer. Current therapies for colon cancer are not very effective and the median survival for patients with metastatic disease is poor at 7-12 months. It is therefore important to increase our understanding of the biology underlying these inflammatory conditions so that more effective treatments may be developed and fewer patients proceed to the cancerous stage. We have recently demonstrated a novel interaction between two proteins that may be relevant to intestinal inflammation. Surprisingly, the two proteins would not normally be expected to coincide with each other because of their different localisations within cells and tissues. The first protein, Cdx2, is only synthesised by intestinal lining cells and normally resides in the nucleus where it activates genes that play a role in the highly specialised absorptive functions of the intestine. The other protein, acrogranin-granulin, is more widely distributed in the body and is generally transported out of cells shortly after it has been made. It has been shown to interact with receptors on epithelial cells and blood cells and promotes their growth. In this proposal we will be investigating whether the complex formed between Cdx2 and granulin is important for normal physiology. Moreover since elevated levels of granulin are associated with inflammation, we aim to determine whether the Cdx2-granulin complex is formed during the active phase of ulcerative colitis and Crohn's disease. Specifically, we will test the hypothesis that the Cdx2-granulin complex plays an important role in repairing the damage caused to the lining of the intestine during inflammation.

溃疡性结肠炎和克罗恩病是使人衰弱的肠道炎性疾病。保守估计（澳大利亚克罗恩病和结肠炎协会）表明，至少有23，000名澳大利亚人受到影响（千分之一）。在发病后10年，估计全结肠炎患者发展为全结肠癌的风险为每年0.5-1.0%。目前结肠癌的治疗不是很有效，转移性疾病患者的中位生存期很差，为7-12个月。因此，重要的是增加我们对这些炎症性疾病背后的生物学的理解，以便开发更有效的治疗方法，减少进入癌症阶段的患者。我们最近证明了两种蛋白质之间的一种新的相互作用，可能与肠道炎症有关。令人惊讶的是，由于这两种蛋白质在细胞和组织中的位置不同，通常预计它们不会彼此重合。第一种蛋白质Cdx 2仅由肠道衬里细胞合成，通常存在于细胞核中，在那里它激活在肠道高度专门化的吸收功能中发挥作用的基因。另一种蛋白质，顶粒蛋白-颗粒蛋白，在体内分布更广泛，通常在产生后不久就被运输出细胞。它已被证明与上皮细胞和血细胞上的受体相互作用，并促进它们的生长。在这项提案中，我们将研究Cdx 2和颗粒蛋白之间形成的复合物是否对正常生理学很重要。此外，由于颗粒蛋白水平升高与炎症相关，我们的目标是确定Cdx 2-颗粒蛋白复合物是否在溃疡性结肠炎和克罗恩病的活动期形成。具体来说，我们将测试Cdx 2-颗粒蛋白复合物在修复炎症过程中对肠道内壁造成的损伤中起重要作用的假设。