Evaluate novel genetic mechanisms of atherosclerosis
In this project, we use genome-wide association studies as a tool to identify novel non-lipid mechanisms of atherosclerotic cardiovascular disease. We apply state of the art computational approaches, including methods that we have developed to make predictions on novel genes and variants that affect vascular tissue integrity, function or differentiation and we then study their mechanisms in-vitro and in-vivo using genome engineering approaches.
Study the genetic underpinnings of extreme phenotypes in vascular disease
In this translational research project, we go from bedside to bench. We enroll patients and families with extreme phenotypes of atherosclerosis - either premature disease without traditional risk factors or lack of any evidence of subclinical disease despite familial hyperlipidemia syndromes. We sequence their genome and perform single cell sequencing of target vascular and immune tissues to discover the genetic mechanisms that underlie those unusual clinical presentations. We then study our findings in the lab to further characterize the involved pathways.
Discover the genetic mechanisms that govern human biological aging
Every person ages differently. The mechanisms of human aging are incompletely understood but the accumulation of somatic variants in our cells is thought to underlie most processes involved in aging. In this project, we derive the rate of somatic variant accumulation from human Whole Genome Sequences in TOPMed, a large population genetics consortium. We use that rate to derive a biological aging clock for each individual and we study how germline variation and environmental factors contribute to biological aging.
Explore the biology of endothelial development
The vascular endothelium is the primary protective layer of our vascular bed. Besides a barrier function the endothelium is involved in multiple biological processes, including immune regulation, paracrine signaling, vesicular trafficking and lipid metabolism. Those roles are facilitated by endothelial specialization during differentiation and cell state transitions that occur in response to stimuli. In this project, we use human single cell RNA-seq data and in vitro perturb-seq experiments to define the transcription factor orchestrators of endothelial differentiation and specialization.