This web page was produced as an assignment for Genetics 677, an undergraduate course at UW-Madison.
Conclusion
From Gen677 long semester project, I learned a lot about BMPR2 in general. When I started this project, I briefly knew about the biomechanical study based on the arterial remodeling due to accumulation of smooth muscle cells in pulmonary artery. However, from studying of this human disease "Pulmonary Arterial Hypertension" from genetical perspective, I now understand what is the fundamental cause to lead arterial remodeling.
Based on what I found in homology and protein domain, the gene and protein of BMPR2 is well conserved throughout different species. As expected, Chimpanzee is the most closest organism to human based on my protein. In addition, mouse also shows highly positive correlation with human protein, which is about 98%. Because the protein domains are well conserved, many genetics or biomechanical studies are conducted with mice. Furthermore, information I gained from Amigo about gene ontology was useful to understand the roles that BMPR2 plays. In addition, visualizing protein interaction with various database really helped to understand and also to give an idea my furture directions. What I learned from protein interaction based on my figures I posted in "ptotein interaction" page and journal articles, ligands (BMPs) bind to BMPR2 to phosphorylate. This phosphorylation is involved with protein kinase domain, which is a serine/threonine kinase (presented as STKs from Smart). The signal continuously passes down to next protein by phosphorylation. As a consequence, BMPR1 phosphorylates Smad1, which has a function of inhibiting smooth muscle cell proliferations. Therefore, STKs domain or protein kinase domain is an important thing to consider as in terms of carrying proper function or of mutation. Furthermore, I attempted to find any new information based on other organisms database for my RNAi source. However, I could not find any things that might be suitable for my project. Lastly, using microarray to look at gene expression is a great experimental tool to carry my project. I could not really find exact microarray that maybe helpful for my project. But the only that I found and posted under" microarray" shows the proliferation of smooth muscle cells in the diseased state. If I actually run microarray to compare normal and mutated BMPR2, I expected to see different gene expression that may be give clues for my future directions. Maybe it is going to be useful to determine which proteins may be involved in terms of developing into pulmonary arterial hypertension.
In a personal conclusion, I think it is necessary to study with various scientific fields other than clinical trials, such as genetical approach. By studying genetical information about the gene and the protein of BMPR2, it will open another opportunity to improve treatment and cure for this rare condition human disease.
Future Directions
From my research project, I learned the basic function of BMPR2 does as a receptor. When ligand, such as BMP4, BMP7, or other BMPs, binds to BMPR2, it is activated by phosphorylation. This phosphorylation is involved with protein kinase domain, which is a serine/threonine kinase. The signal continuously is passed down to next protein by phosphorylation. As a consequence, BMPR1 phosphorylates Smad1, which has a function of inhibiting smooth muscle cell proliferations. However, when BMPR2 is mutated, the signaling pathway is blocked due to inhibition of phosphorylation. Based on what I understand, there is an alternative way that ligand binds with. For example, when BMP ligand fails binding to BMPR2, it binds with TFG-βR2. Therefore, TFG-βR2 phosphorylates TFG-βR1 that further phosphorylates Smad2 instead of Smad1 (Morrell 2006). Unlike Smad1, Smad2 prefers proliferation of smooth muscle cell (Yang et al 2005). Therefore, I would like to investigate whether there is significant different level of smooth muscle cell between normal and BMPR2 mutation. My question of next project is whether Smad signaling plays a role in smooth muscle cell proliferation in blood vessel to make narrow diameter. To make detail scheme of the future experiment, I would like to test the level of smooth muscle cell in both normal and BMPR2 mutation. If there is any difference, I would like to move to next step, which is to test the level of smooth muscle cell in different state of Smads. For example, I can use mouse with phosphorylated Smad1, de-phosphorylated Smad1, phosphorylated Smad2, and de-phosphorylated Smad2. In order to measure the level of smooth muscle cells, I can stain the cells to count and to measure mouse pulmonary artery’s diameter. I am expecting to see many smooth muscle cells and the narrowest diameter of pulmonary artery from the mouse model with phosphorylated Smad2. Because activated Smad2 favors smooth muscle cell proliferation, I think this model will reflect the most active proliferation. If all experiments are turned out great as I expected, I would like to investigate more about detail signaling how BMPR2 is working. In addition, because penatrance of this disease is very low (20-30%), it would be nice to look for other proteins or any other environmental conditions that might be involved with (Morrell 2006).
From my independent project in Genetics 677 at the University of Wisconsin-Madison, I learned a lot in terms of understanding basis of genomics and proteomics, the usage of database, and its application to my own project. I really enjoyed my class academically and personally. I believe what I’ve learned from this class will help me a lot when I go to graduate school next year! This was a great experience for me to understand the disease better and to enjoy genomic/proteomic class!
Here is my final presentation that includes detail experimental proposal for my future study. The presentation includes more references in order to understand the disease and the gene better.
FINAL PRESENTATION by AH RAM KIM (GENETICS 677)
From Gen677 long semester project, I learned a lot about BMPR2 in general. When I started this project, I briefly knew about the biomechanical study based on the arterial remodeling due to accumulation of smooth muscle cells in pulmonary artery. However, from studying of this human disease "Pulmonary Arterial Hypertension" from genetical perspective, I now understand what is the fundamental cause to lead arterial remodeling.
Based on what I found in homology and protein domain, the gene and protein of BMPR2 is well conserved throughout different species. As expected, Chimpanzee is the most closest organism to human based on my protein. In addition, mouse also shows highly positive correlation with human protein, which is about 98%. Because the protein domains are well conserved, many genetics or biomechanical studies are conducted with mice. Furthermore, information I gained from Amigo about gene ontology was useful to understand the roles that BMPR2 plays. In addition, visualizing protein interaction with various database really helped to understand and also to give an idea my furture directions. What I learned from protein interaction based on my figures I posted in "ptotein interaction" page and journal articles, ligands (BMPs) bind to BMPR2 to phosphorylate. This phosphorylation is involved with protein kinase domain, which is a serine/threonine kinase (presented as STKs from Smart). The signal continuously passes down to next protein by phosphorylation. As a consequence, BMPR1 phosphorylates Smad1, which has a function of inhibiting smooth muscle cell proliferations. Therefore, STKs domain or protein kinase domain is an important thing to consider as in terms of carrying proper function or of mutation. Furthermore, I attempted to find any new information based on other organisms database for my RNAi source. However, I could not find any things that might be suitable for my project. Lastly, using microarray to look at gene expression is a great experimental tool to carry my project. I could not really find exact microarray that maybe helpful for my project. But the only that I found and posted under" microarray" shows the proliferation of smooth muscle cells in the diseased state. If I actually run microarray to compare normal and mutated BMPR2, I expected to see different gene expression that may be give clues for my future directions. Maybe it is going to be useful to determine which proteins may be involved in terms of developing into pulmonary arterial hypertension.
In a personal conclusion, I think it is necessary to study with various scientific fields other than clinical trials, such as genetical approach. By studying genetical information about the gene and the protein of BMPR2, it will open another opportunity to improve treatment and cure for this rare condition human disease.
Future Directions
From my research project, I learned the basic function of BMPR2 does as a receptor. When ligand, such as BMP4, BMP7, or other BMPs, binds to BMPR2, it is activated by phosphorylation. This phosphorylation is involved with protein kinase domain, which is a serine/threonine kinase. The signal continuously is passed down to next protein by phosphorylation. As a consequence, BMPR1 phosphorylates Smad1, which has a function of inhibiting smooth muscle cell proliferations. However, when BMPR2 is mutated, the signaling pathway is blocked due to inhibition of phosphorylation. Based on what I understand, there is an alternative way that ligand binds with. For example, when BMP ligand fails binding to BMPR2, it binds with TFG-βR2. Therefore, TFG-βR2 phosphorylates TFG-βR1 that further phosphorylates Smad2 instead of Smad1 (Morrell 2006). Unlike Smad1, Smad2 prefers proliferation of smooth muscle cell (Yang et al 2005). Therefore, I would like to investigate whether there is significant different level of smooth muscle cell between normal and BMPR2 mutation. My question of next project is whether Smad signaling plays a role in smooth muscle cell proliferation in blood vessel to make narrow diameter. To make detail scheme of the future experiment, I would like to test the level of smooth muscle cell in both normal and BMPR2 mutation. If there is any difference, I would like to move to next step, which is to test the level of smooth muscle cell in different state of Smads. For example, I can use mouse with phosphorylated Smad1, de-phosphorylated Smad1, phosphorylated Smad2, and de-phosphorylated Smad2. In order to measure the level of smooth muscle cells, I can stain the cells to count and to measure mouse pulmonary artery’s diameter. I am expecting to see many smooth muscle cells and the narrowest diameter of pulmonary artery from the mouse model with phosphorylated Smad2. Because activated Smad2 favors smooth muscle cell proliferation, I think this model will reflect the most active proliferation. If all experiments are turned out great as I expected, I would like to investigate more about detail signaling how BMPR2 is working. In addition, because penatrance of this disease is very low (20-30%), it would be nice to look for other proteins or any other environmental conditions that might be involved with (Morrell 2006).
From my independent project in Genetics 677 at the University of Wisconsin-Madison, I learned a lot in terms of understanding basis of genomics and proteomics, the usage of database, and its application to my own project. I really enjoyed my class academically and personally. I believe what I’ve learned from this class will help me a lot when I go to graduate school next year! This was a great experience for me to understand the disease better and to enjoy genomic/proteomic class!
Here is my final presentation that includes detail experimental proposal for my future study. The presentation includes more references in order to understand the disease and the gene better.
FINAL PRESENTATION by AH RAM KIM (GENETICS 677)
| bmpr2_presentation_ah_ram_kim.pdf |
References
[1] Morrell, N. (2006) Pulmonary Hypertension Due to BMPR2 Mutation. Proc Am Thorac Soc3, 680-686. doi: 10.1513/pats.200605-118SF
[2] Yang, X, Long, L., Southwood, M., Rudarakanchana, N., Upton, P., Jeffery, T., Atkinson, C., Chen, H., Trembath, R., & Morrell, N. Dysfunctional Smad Signaling Contributes to Abnormal Smooth Muscle Cell Proliferation in Familial Pulmonary Arterial Hypertension. Circulation Research 96, 1053-1063.
doi: 10.1161/01Res0000166926.54293.68
[1] Morrell, N. (2006) Pulmonary Hypertension Due to BMPR2 Mutation. Proc Am Thorac Soc3, 680-686. doi: 10.1513/pats.200605-118SF
[2] Yang, X, Long, L., Southwood, M., Rudarakanchana, N., Upton, P., Jeffery, T., Atkinson, C., Chen, H., Trembath, R., & Morrell, N. Dysfunctional Smad Signaling Contributes to Abnormal Smooth Muscle Cell Proliferation in Familial Pulmonary Arterial Hypertension. Circulation Research 96, 1053-1063.
doi: 10.1161/01Res0000166926.54293.68
