Calum MacRae, MD, PhD
Harvard Medical School
Our lab is interested in the role of functional inputs such as mechanical forces, metabolism or electrical activity in refining the basic programs of cell specification and differentiation in cardiovascular development, disease, repair and regeneration.
In a multidisciplinary approach to these problems, involving group members who are geneticists, developmental biologists, physiologists, computational biologists and engineers, we are working in three main areas;
Unraveling the role of functional remodeling in the heart and vascular system - The basic cellular plan of the heart and vascular networks undergoes tremendous regional specialization during development. For example, gradients of myocyte function exist between the endocardium and epicardium, while each organ has a distinctive arterial or venous endothelium. Using the zebrafish and chick, we are combining classic developmental cell and molecular biology with high resolution in vivo cellular physiology to understand how genetic and epigenetic factors interact to generate this cellular diversity in conjunction with the genetic programs regulating organogenesis. Current projects include the generation of a functional fate map of the early heart, and dissecting the role of physiologic stimuli such as mechanical or electrical signals in the patterning of the heart and vasculature.
Systems level disease modeling in the zebrafish – The zebrafish is uniquely positioned as a vertebrate model amenable to high-throughput screening. We have developed robust, automated in vivo assays that enable us to phenotype cellular or integrated cardiovascular function in 96 or 384 well plates. These tools facilitate quantitative, scalable approaches to disease pathway dissection in genetic models of human cardiac and vascular disorders. Genetic screens are underway in these disease models to identify novel pathway members and to explore gene-environment interactions, in particular pharmacogenetics. Parallel screens of small molecule libraries are designed to identify probes for chemical biology strategies in these same diseases with the ultimate aim of identifying new therapeutics.
Genetics of human heart failure – We are also attempting to understand the genetics of common human cardiac and vascular disease. These syndromes have long been viewed as genetically “complex”, but we have based our work on the premise that much of the apparent complexity reflects limited phenotypic resolution. In our human studies we are reevaluating disease phenotypes in classic kin-cohorts to resolve the genetic architecture of heart failure and vascular disease. These cohorts also enable investigation of early pathophysiologic mechanisms in ‘preclinical’ individuals (and in cells derived from these individuals), offering an avenue for the rapid translation of new diagnostic or therapeutic approaches.