Describe how and why you chose your iGEM project.
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Brain is one of the most important organs of human beings, no matter whether the tumor in the brain is benign or malignant, once it compresses any part of the brain, it will affect the health of human body.
Recently, the incidence of intracranial tumors has been on the rise. According to statistics, intracranial tumors account for about 5% of total body tumors and 70% of childhood tumors, while other malignant tumors will eventually have 20-30% transferred into the intracranial. Due to its expansive and invasive growth, once the intracranial occupies a certain space, no matter whether it is benign or malignant in nature, it will inevitably increase intracranial pressure, so as to lead to central nervous damage and endanger the patient's life.
The most effective treatment for brain tumors is surgical removal of the tumor. Most malignant brain tumors can’t be completely surgically cut off and will regrow. Therefore, using some tracer to track the tumor is an important process in healing the patients.
As a reliable, sensitive, convenient and non-invasive in vivo imaging technology, bioluminescence imaging (BLI) has been extensively applied in detecting physiological and pathological processes in biomedical research, including pathogen detection, tumor growth and responses to therapy patterns of gene regulation, measurements of protein–protein interactions and ADMET (absorption, distribution, metabolism, excretion and toxicity). Among various bioluminescence systems, firefly luciferase-luciferin is powerful and popular to noninvasively visualize molecular and cellular features in living mice. Some drawbacks of natural substrates D-luciferin and aminoluciferin, however, hamper the application of bioluminescent imaging with firefly luciferase, such as short red-light (tissue-penetrating) emission, short in vivo bioluminescence time and low blood-brain barrier permeability.
In the current study, we will develop the cyclic N-aminoluciferins as reasonable firefly luciferase substrates with enhanced lipid solubility from aminoluciferin. We propose to prepare the cyclic N-aminoluciferins with high lipid solubility derived from aminoluciferin. Using various cyclic amines as a starting material, several novel firefly luciferase substrates will be generated after a cyclization reaction.
We are going to complete bioluminescence emission spectra assay, in vitro bioluminescence assay, cell bioluminescence imaging, nude xenograft tumor mice imaging, FVB-Tg transgenic mice imaging and brain bioluminescence imaging of nude mice to detect if the cyclic N-aminoluciferins with high lipid solubility will be able to overcome problems like short red-light (tissue-penetrating) emission, short in vivo bioluminescence time and low blood-brain barrier permeability.
By modifying the chemical groups of the luciferase substrate, we might enhance many of the substrate‘s properties, as well as reach many exciting conclusions. If our experiments could prove our hypothesis, our approach will facilitate the direct interrogation of cancer progression for filling a long-standing void in live animal imaging capabilities not currently possible with existing toolsets. We believe that these novel firefly luciferase substrates will expand the repertoire of the family of existing bioluminescence imaging tools and may fundamentally change existing views on brain cancer progression and therapeutic approaches.
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