Characterisation of a new mechanism of regulation for HIF1 and the hypoxic response.

我相信我们在BBSRC的记录和我们的出版物表明，我们可以实现这个令人兴奋的项目的目标，并成功地返还这笔赠款，并对LIMD1生物学和HIF信号通路提出新的和重要的见解和进展。这被称为“氧稳态”，在动物和所有多细胞生物体中都受到严格的调控，以确保组织获得足够的氧气供应。虽然人体内的氧气水平从上呼吸道的21%到大多数器官的平均5%不等，但每种组织类型都有一定的氧气需求，低于一定浓度的氧气会损害基本的细胞过程，如能量产生、蛋白质合成以及细胞生长和分裂。细胞或组织对低氧浓度(‘低氧’)的快速反应和适应可以使细胞保持存活，从而减少对生物体的潜在损害。这就是所谓的“缺氧性反应”。缺氧反应的解除是癌症发展的一个关键特征，也是大肿瘤生长及其在全身扩散的一个关键特征。此外，这一关键的细胞控制过程的放松也与许多非癌症疾病有关，如神经系统疾病、心肌梗死(心脏病发作)、中风和许多与缺血(低氧)相关的疾病。因此，对这一关键的细胞调控过程的分子生物学的完整理解仍然是世界范围内基础细胞和分子生物学研究的重要焦点。为此，我们最近发现了一种名为LIMD1的蛋白质，它对调节缺氧反应的正常功能至关重要。此外，我们已经证明，这种蛋白的丢失在细胞内创建了一个假缺氧环境，导致它的反应就像是处于上述缺氧性疾病状态之一。因此，我们的发现代表了一个新的未知的分子生物学水平，对低氧反应至关重要。此外，我们目前是世界上唯一一个研究这一特定领域的低氧调节的组织，希望有了BBSRC奖，我们可以继续研究这一令人兴奋的新分子生物学。此外，这些信息将为该领域的基础和临床分子生物学研究人员提供一条主要的新途径，并为未来开发与缺氧性疾病相关的药物治疗和治疗提供一套新的蛋白质靶点。

I believe our track record with the BBSRC and our publications demonstrate we can achieve the goals of this exciting project and successfully return this grant with novel and significant insights and advances to LIMD1 biology and the HIF signalling pathway.Optimum levels of oxygen are required throughout the cells and tissues of our body for survival. Referred to as 'oxygen homeostasis', this is tightly regulated in animals and indeed all multicellular organisms to ensure that tissues are sufficiently supplied with oxygen. Whilst oxygen levels range within the human body from 21% in the upper airway to an average of 5% in most organs, each tissue type has a requirement for a certain concentration of oxygen, below which essential cellular processes such as energy production, protein synthesis and cell growth and division become impaired. Rapid reaction and adaptation of a cell or tissue to low oxygen concentrations ('hypoxia') can enable cells to remain viable, thus reducing potential damage to the organism. This is known as the 'hypoxic response'. Deregulation of the hypoxic response is a key characteristic in cancer development and also large tumour growth and its spread throughout the body. Furthermore, deregulation of this key cellular control process is also linked to many non-cancerous diseases such as neurological disease, myocardial infarction (heart attacks), stokes, and many ischemic (low oxygen) related diseases. Therefore, a complete understanding of the molecular biology of this critical cellular control process remains an important focus for basic cell and molecular biology research worldwide. To this end we have recently identified a protein called LIMD1 that is a critical to regulating the normal function of the hypoxic response. Furthermore, we have shown that loss of this protein creates a pseudo-hypoxic environment within the cell, causing it to react as if it is in one of the hypoxic diseased states mentioned above. Our discovery therefore represents a new unknown level of molecular biology critical for the hypoxic response. Moreover, we are currently the only group in the world to be researching this specific area of hypoxic regulation, and hopefully with this BBSRC award, we can continue to investigate this exciting new molecular biology. Furthermore, such information will represent a major new avenue of investigation to basic and clinical molecular biological researchers in this field and represent a new set of protein targets for future development of hypoxic disease-related drug therapies and treatments.