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

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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.