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| Cardiomyogenesis Studies |
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Research is directed at discovering molecules that promote differentiation of cardiomyocyte progenitors that will ultimately be useful for regeneration of muscle cells that are lost in heart disease. To do this, we 1) study heart formation during embryonic development to learn about the natural cell and tissue interactions that control heart formation, 2) study cardiomyocyte differentiation in mouse and human embryonic stem cells (ESCs) and induced pluripotent stem cells (IPSCs), and 3) use screening approaches to discover small molecules for cardiomyocyte production from ESCs.
Recent studies from the laboratory led to the discovery of signaling cascades that specify cardiogenic mesoderm in the early embryo and, subsequently, control the formation of certain cardiac tissues, such as heart muscle cells. Signaling cascades initiated by Wnt, BMP and Notch proteins, and continued by lesser-known function proteins such as Nkx2.5, are critical, as are complex interactions with tissues outside the heart field such as cells of the developing nervous system. Knowledge of the pathways that produce heart tissue in embryos is being applied to increase cardiomyogenesis efficiency for regenerative medicine applications.
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Bioinformatics and Systems Biology, Subramaniam Lab
Biomaterials and Stem Cell Engineering, Varghese Lab
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| Discovery of Links Between Post-Translational Modifications and Diseases |
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Proteins are responsible for maintaining functional stability and homeostasis of cells and tissues. During aging there are many opportunities for appropriately transcribed proteins to become structurally altered. Accumulation of altered proteins may correlate with inappropriate function. Therefore, it is critical to identify the specific alterations of proteins occurring during aging and in disease processes, and to define the role these alterations play in age-related and disease-related pathologies. For example, compaction of structural proteins and decreased hydration during aging has been found to be responsible for altered skin morphologic and mechanical properties manifested as wrinkling and loss of elasticity.
One important form of structural variation is post-translational modification. It is essential to know more about how proteins are post-translationally modified under native and abnormal conditions, and how this is correlates with disease.
I have developed an approach to the prediction and experimental verification of protein structure and consequently function modification in disease states. By combining various data sources, associating highly co-occurring entries, and providing a confidence score to significant associations, it is possible to yield a list of candidate post-translational modifications which are associated to specific genes/proteins and aging-related pathologies, such as Alzheimer's or arthritis. The high-scoring candidates in this set are now being verified through specific experimental studies, based on similar studies that have previously proven to be successful. Results will provide an understanding of the molecular changes that take place in specific proteins during age-related disorders.
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| Association of Protein Mutation with Functional Flexibility |
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Recently, the Bourne Lab at UCSD developed a program for predictiong functional flexibility of proteins (Wiggle). Currently, statistical studies are undergoing to determine whether point mutations are more likely than non-mutant positions to incur functional flexibility among kinases. In the future, studies will be expanded to other types of mutations, such as indels, and other types of proteins, such as HIV proteases.
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