Asthma Foundation/ School Of Biomedical Science Honours Bursary Award - Research Proposal Example

?BIOM3200 Research Proposal Template APPLICANT DETAILS Number: Proposal Asthma Foundation/ School of Biomedical Science Honours Bursary Award Do you wish to be considered for an Asthma Honours Bursary award (Yes/ No): If YES, please indicate the topic you would like to study and/ or the researcher you would like to work with (state “undecided” if not yet known): Abstract/ Synopsis (250 words maximum) Asthma, a chronic inflammatory disease of the lungs is a physical health condition that is highly associated with the production of mucins MUC5AC and MUC5B. Too much of these mucus as indicated in the overproduction of goblet cells in the airways have been found to promote discomfort and even complexities that may eventually lead to death. Asthma is remarkably identified as a disease that promotes expression of NRG and IFN, the special proteins of the body that will be produced in the presence of pathogens and other related microorganisms to stand as body’s defense system. Concerning this, there are wide variety of research studies associated with the overproduction of mucins and even the suppression of potential factors that may lead to the vital treatment. Regarding this, this research study will try to employ asthmatic mice models to measure the potential level of EGF when NRG will be either knocked out or not. This will also lead to consideration whether mucins like MUC5B protein expression will be lower in NRG asthmatic mice models compared to the NRG knocked out mice models. This study will substantially reveal potential sophisticated way in order to provide modern therapeutic way to combat asthma. In order to do this, NRG must provide evidence of therapeutic trend, by studying relevant factors that may lead to increase the level of its production in the mice models. Furthermore, a relevant research design must adhere to some previous studies that at some point provide the essential foundation for the background of this research investigation. lay person summary (150 words maximum) A relevant evidence of the existence of asthma might be the overproduction of mucus in the airways in the respiratory system. Such medical condition requires a necessary attention because of a higher possibility of potential death. For this reason, it is important to understand some factors that will help us understand the possible ways to prevent overproduction of mucus in the lungs. This study will seek to investigate this point to find the novel evidence that will provide the opportunity for a modern approach in the treatment of asthma, and possibly in other related respiratory disease of the lungs. To do this, the proponent will employ asthmatic mice models to find for significant factors that will lead to the treatment of asthma. Important consideration is to understand the biological concepts in line with how the body will react to pathogens. Special proteins are considered for this matter. Background (1000 words maximum) This section must be referenced appropriately. Subheadings can be used at your discretion. Receptor tyrosine-protein kinase erbB is an enzyme that in the case of humans is encoded by the ErbB gene. The ErbB2 gene was found to provide receptors that pave the way for the maximum functioning of proteins like NRG1b1-induced expression of MU5AC and MU5AB (Kettle et al., 2010). Concerning this, neuregulins (NRGs) are “cell-cell signalling proteins that are ligans for receptor tyrosine kinases of the ErbB family” (Falls, 2003). This family of genes has four members including NRG1, NRG2, NRG3 and NRG4 and little has been known about the biological functions of the last three proteins, except for the NRG1 which has been found to play an elemental role in the nervous system, heart and breast (Falls, 2003). However, there are some evidences to suggest that NRG has significant participation when there is formation of pathogens and cancer cells like in the case of pathogenesis of schizophrenia, breast cancer and neuropathic pains (Falls, 2003; Tao et al., 2013). However, NRG may not only play an essential role in the above-mentioned health problems like cancers. In some studies, the cell-cell signalling function of NRG might be observed from the human’s body’s defence mechanism. Specifically, for instance, this is something that might influence the viscoelastic property of mucus in various cases linked to respiratory health problems like asthma. To understand this point further, it is necessary to take a look at the basic function of mucins. Mucins are known to possess these functions which include cell-cell interaction, epidermal growth factor receptor signalling, and airways protection. This means that mucins help trap inhaled microbial organism, particulates and oxidative pollutants, linking them to various lung diseases like asthma, chronic obstructive pulmonary disease, cystic fibrosis, emphysema and lung cancer (Thai, Loukoianov, Wachi & Wu, 2008). The mucins, particularly MUC5AC and MUC5B are rich in their production among individuals with chronic respiratory diseases leading to the viscoelastic property of mucus, which triggers potential problems in the respiratory airways (Kettle et al., 2010). It is therefore important to find out what exactly regulates these mucins so as to provide substantial relief and even a novel therapy for any related respiratory problems involving pathogens and activities linked to various gene expressions. It was found that Thelper type 2 cytokine, IL-13, regulates MUC5AC expression in goblet cells of the airways, but little is known what regulates MUC5B expression, which led to a study finding that neuregulin 1?1 is a mediator of MUC5AC and MUC5B mucin expression, creating a remarkable claim, though not yet conclusive for therapeutic applications in asthma and chronic obstructive pulmonary disease (Kettle et al., 2010). The overproduction of mucus, especially in the expression of MUC5AC has been reported in as certain study to have a corresponding link with goblet cells, which also has been found to potentially associate with oxidative stress and epidermal growth factor receptor (EGFR) (Matsuda, Monzon & Forteza, 2006). To measure this, the said research study tried to assess EGFR activation and signaling by measuring EGF. Therefore, there is a need to inhibit something to which the NRG binds to. As learned previously NRG increases as mucus expression might potentially increase, which paves the idea that there is a need to inhibit the receptor. In other words, there is a need to inhibit the receptor that NRG binds to so as might end up decreasing MUC5AC expression, at some point. From an experimental design, ErbB3 can be inhibited in order that NRG1-beta cannot bind to this receptor, preventing the upregulation of MUC5AC and MUC5B (Yu et al., 2011). Another study reveals that ErbB3 was knocked down by small interference RNA (siRNA) blunted the effects of HRG (Gon et al., 2011). This could potentially decrease the mucus production, at some certain level. On the other hand, another study concerning chronic inflammatory diseases of the lungs like asthma claims that IFN-? has the potential to modulate the effects of IL-13 in the lungs when wild-type mice were given recombinant cytokines intranasally, and it was found that IFN-? inhibited IL-13 induced goblet cell hyperplasia and airway eosinophilia, and even IFN-? and IL-13 increased the effectiveness of each other’s effects (Ford et al., 2001). Interferons (IFNs) are proteins that come up when there is presence of pathogens or tumour cells. For this matter, interferon gamma (IFN-?) was found to have vital role in various lung inflammatory responses (Pawliczak et al., 2005). Now remarkably, there is a clue that NRGs may have potential role in the chronic inflammatory diseases of the lungs like asthma. At the same time, IFNs were found to provide elemental part in lung inflammatory responses. For this reason, it is important to find how NRG, a gene identified by GWAS based on the preliminary data plays a part in IFN expression when an individual is in contact with viral infections, pathogens and even asthma. This will eventually create a very important idea that will help prove if NRG has significant relationship with asthma. Furthermore, such idea will provide the opportunity to explore any possible novel therapeutic role of NRG in the treatment of asthma. preliminary data (500 words maximum) This section should contain text and figures as appropriate. The preliminary analysis of the GWAS data revealed that there was an association between a mutation near the gene encoding the expression of NRG and the asthma phenotype. There were two series of experiments initiated. The two experiments reveal that virus infection shows an increase in NRG for mRNA expressions as illustrated in Figure 1. However, when NRG is downregulated, the IFN- ? expression increases. When NRG is knocked out IFN expression is higher. Based on the previous discussion, IFN is known to resist virus infections or any pathogens entering the body. This therefore suggests that NRG might have a therapeutic role for asthma. Mucus hyposecretion is linked to asthma, which eventually brings the idea that NRG might play a significant role in the context of creating a relevant therapeutic proof. Figure 1. The level of NRG mRNA concentration of the two groups of mice. The first group was not exposed to viral infection, while the second group was exposed to a viral infection. Figure 2. The level of IFN- ? expression when NRG is downregulated. experimental design & rationale (1000 words maximum) Experiments should address the stated hypotheses and aims. The purpose of this research study is to find the possible novel therapeutic role of Neuregulin in asthma. In particular, the proponent wants to know the essential role of NRG in IFN expression when there is exposure to viral or pathogens linked to asthma. For this reason, there is a strong point to consider the possible therapeutic influence of NRG for asthma. This study will need to investigate if there is potential link between the levels of IFN and NRG expression knowing that based on the preliminary experiment the presence of viral pathogens in the body will tend to affect the level of NRG expression. If there is a significant correlation, then it is of great concern to investigate further what important factors may trigger such formation of relevant association. This research study will employ a correlational analysis that will aid in the analysis of the exact relationship that may potentially exist between the level of IFN expression and NRG expression. The following hypotheses will be tested in this study. 1. In NRG asthmatic mice models, there will be lower level of EGF compared to the NRG knocked out models. 2. MUC5 protein expression levels will be lower in NRG asthmatic mice models compared to the NRG knocked out mice models. To test these hypotheses, first, there is a need to knock out NRG in one group of mice, but leave NRG alone in the other group. The next step is to induce asthma in mice models by using OVA and let all mice to fully recover. Materials and methods will be based on the study of Zhang, Li and Guo (2012). The next move will be to follow the guidelines in experiment 1 for the preliminary experiment using PVM. The description is presented in Figure 3 below. Finally, the mice’s EGF protein expression levels should be measured. Cells might be incubated and pretreated with the selective tyrosine kinase inhibitors (Takeyama et al., 1999). Figure 3. The description of NRG Experiment 1 with PVM. EXPECTED OUTCOMEs AND Significance (500 words maximum) This section must be referenced appropriately. Asthma is one of the leading causes of death around the world especially in cases in line with chronic inflammatory diseases of the lungs (Reed, 1999; Bergstrom et al., 2008). This disease does not only bring physical discomfort, but aside from that it requires treatment that may be recurring from time to time leading to a vast considerable monetary expense (Reed, 2006; Weinberger, 2004). In order to find a reasonable and even a more sophisticated approach in the treatment of asthma, a novel research study is necessary concerning this point. It is found that NRG may have a vital role in the mucus production for asthma, and downregulation of EGF or IL-13 with NRG might provide a new breakthrough for the advancement in the treatment of asthma (Takeyama et al., 1999; Ford et al., 2001). For this reason, this research study will hope to find that there will be a significant correlation between the levels of EGF and NRG. Furthermore, mucus expression will have a significant relationship with the presence of NRG in the mice models. References Bergstrom, S. E., Boman, G., Eriksson, L., Formgren, H., Foucard, T., Horte, L. G., Janson, C., Nystrom, U. S., & Hedlin, G. Asthma mortality among Swedish children and young adults, a 10-year study. Respiratory Medicine, 102(9), 1335-1341. Falls, D. L. (2003). Neuregulins: functions, forms, and signalling strategies. Experimental Cell Research, 284(1), 14-30. Ford, J. G., Rennick, D., Donaldson, D. D., Venkayya, R., McArthur, C., Hansell, E., Kurup, V. P., Warnock, M., & Grunig, G. (2001). IL-13 and IFN-?: Interactions in Lung Inflammation. The Journal of Immunology, 167, 1769-1777. Gon, Y., Matsumoto, K., Terakado, M., Sekiyama, A., Maruoka, S., Takeshita, I., Kozu, Y., Okayama, Y., Ra, C., & Hashimoto, S. (2011). Heregulin activation of ErbB2/ErbB3 signaling potentiates the integrity of airway epithelial barrier. Experimental Cell Research, 317, 1947-1953. Kettle, R., Simmons, J., Schindler, F., Jones, P., Dicker, T., Dubois, G., Giddings, J., Heeke, G. V., & Jones, C. E. (2010). Regulation of Neuregulin 1?1- Induced MUC5AC and MUC5B Expression in Human Airway Epithelium. American Journal of Respiratory Cell Molecular Biology, 42, 472-481. Matsuda, S. M., Monzon, M. E., & Forteza, R. M. (2006). Epidermal Growth Factor Receptor Activation by Epidermal Growth Factor Mediates Oxidant-Induced Goblet Cell Metaplasia in Human Airway Epithelium. American Journal Respiratory Cell Molecular Biology, 34, 581-591. Pawliczak, R., Logun, C., Madara, P., Barb, J., Suffredini, A. F., Munson, P. J., Danner, R. L., & Shelhameri, J. H. (2005). Influence of IFN-? on gene expression in normal huma bronchial epithelial cells: modulation of IFN-? effects by dexamethasone. Physiological Genomics, 23, 28-45. Reed, C. 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Drug Discovery Today, 9(19), 831-837. Yu, H., Li, Q., Kolosov, V. P., Perelman, J. M., & Zhou, X. (2011). Regulation of Cigarette Smoke-Induced Mucin Expression by Neuregulin1-beta/ErbB3 Signalling in Human Airway Epithelial Cell. Basic and Clinical Pharmacology & Toxicology, 109, 63-72. Zhang, J., Li, C., & Guo, S. (2012). Effects of Inhaled Inactivated Mycobacterium phlei on Airway Inflammation in Mouse Asthmatic Models. Journal of Aerosol Medicine and Pulmonary Drug Delivery, 25, 96-103. Read More