Science
Current interests in our group include:
1. Systematic profiling of patient-derived cells via small molecule perturbation and gene expression.
2. Modulating epigenetic modifications during cardiac differentiation using novel small molecules.
3. Developing novel ways to phenotype human subjects, such as cell-based or imaging phenotypes.
Our group works closely with collaborators at MGH, the Broad Institute of Harvard & MIT, the Harvard Stem Cell Institute, and the Framingham Heart Study.
1. Systematic profiling of patient-derived cells
As validated susceptibility alleles are discovered for cardiovascular and metabolic diseases, assigning function to these genetic variants has posed a critical roadblock to clinical translation. Many susceptibility alleles do not lend themselves to study by traditional methods; they may fall within non-coding DNA, or many different SNPs over large distances may contribute to disease susceptibility.
Genetic interaction screens (analogous to those performed in model organisms such as yeast or C. elegans) can identify pathways that functionally interact with disease mutations and thereby help assign function to these alleles. We perform synthetic genetic interaction screens in human cells, by screening for small molecules that exert distinct phenotypes in mutant vs. wild-type patient samples. In parallel, we also profile patient cells using genome-wide gene expression. We are currently studying cells from an extreme form of diabetes, and are extending these efforts to disease susceptibility alleles for cardiovascular disease and diabetes.
Analysis of small molecule and gene expression profiling data can lead to novel ways to phenotype patients at the cellular level, help assign function to disease mutations, and suggest FDA-approved drugs that might be “repurposed” for therapeutic effect (and thus rapidly translated into human applications).
Systematic profiling of patient-derived cells
2. Modulating cardiac differentiation using novel small molecules
Dynamic changes in histone acetylation, DNA methylation, and other epigenetic marks accompany embryonic stem (ES) cell differentiation. Small molecules that modulate these processes can improve the efficiency of both ES cell differentiation and induced pluripotent stem cell (iPS) formation. However, existing agents are non-selective, and are toxic to many cell types.
We have undertaken an approach that uses novel synthetic small molecule libraries that are biased to modulate histone-modifying enzymes. We screen these libraries for their ability to induce cardiac differentiation using high-throughput automated microscopy, and have identified several promising compounds with activity in both murine and human ES cells. Current studies use these novel molecules as probes to illuminate the biology of histone modifications in cardiac differentiation, and may also provide a rationale for epigenetic modulation as an adjunct to regenerative therapies for the heart.
3. Novel cell-based and imaging phenotypes
We are interested in discovering novel ways to phenotype patients at the cellular or molecular level, to improve estimates of prognosis, monitor therapy, and facilitate genotype-phenotype correlations. For instance, through a collaboration with the Framingham Heart Study, we are studying how endothelial progenitor cell (EPC) number correlates with clinical phenotypes and genotype.
Another approach to novel phenotypes is through molecular imaging. Through small molecule modification of iron oxide nanoparticles, we are developing new nanoparticle-based imaging probes against protein targets implicated in atherosclerosis; in a complementary approach, we are also screening for novel imaging agents that preferentially target diseased cells and not healthy ones. The goal of these efforts is new imaging phenotypes for cardiovascular disease that are based on critical early molecular alterations, as opposed to mere anatomical imaging.
Selected Recent Publications
Choy E, Yelensky R, Bonakdar S, Plenge RM, Saxena R, De Jager PL, Shaw SY, Wolfish CS, Slavik JM, Cotsapas C, Rivas M, Dermitzakis ET, Cahir-McFarland E, Kieff E, Hafler D, Daly MJ, and Altshuler D. Genetic analysis of human traits in vitro: Drug response and gene expression in lymphoblastoid cell lines. PLoS Genetics. 2008;under review.
Kelly KA*, Shaw SY*, Kristoff K, Aikawa A, Schreiber SL, and Weissleder R. Nanoparticle targeting to endothelial cells via surface conjugation of small molecules. 2008;under review.
Shaw SY. Chemical biology approaches to molecular imaging. In: Molecular imaging: Principles and practice (R Weissleder, S Gambhir, BD Ross, A Rehemtulla, eds.). Hamilton, Ontario, Canada: BC Decker, Inc.;2008.
Shaw SY, Westly E, Pittet M, Subramanian A, Schreiber SL, Weissleder R. Perturbational profiling of nanomaterial biological activity. Proc Natl Acad Sci USA. 2008;105(21):7387-7392.
Low AF, O'Donnell CJ, Kathiresan S, Everett B, Chae CU, Shaw SY, Ellinor PT, MacRae CA. Aging syndrome genes and premature coronary artery disease. BMC Med Genet. 2005;6:38.
Peterson RT, Shaw SY, Peterson TA, Milan DJ, Zhong TP, Schreiber SL, MacRae CA, Fishman MC. Chemical suppression of a genetic mutation in a zebrafish model of aortic coarctation. Nat Biotechnol. 2004;22(5):595-9. |
