Research Abstract:
The mammalian heart must maintain constant and high levels of ATP to perform its mechanical and electrical functions. To do so, the heart is remarkably resilient, able to oxidize a repertoire of metabolic substrates including fatty acids, glucose, and ketone bodies. Our lab uses systems biology approaches, predominantly in mouse models, to study the molecular mechanisms through which the heart adapts to variations in nutrient composition and availability. These molecular, biochemical, cellular, and computational methods are allowing us to identify the biomarkers and develop mechanistic models that describe the adaptive, or maladaptive, responses of the heart to states like the metabolic syndrome and diabetes. These metabolic states are highly associated with adverse cardiovascular events, and conversely, adverse cardiovascular events are poorly tolerated among individuals with these conditions. Therefore, eliciting the biomarker signatures and molecular mechanisms that underlie the nutritional basis for the manner in which the heart responds to these metabolic states potentially opens avenues for therapeutic personalized nutrition and medical regimens. Using nutritionally and genetically-modified mouse models, our lab deploys both high-throughput and hypothesis-focused strategies in a highly interdisciplinary and collaborative environment: (i) functional genomics: using microarray transcriptional profiles from our datasets, we generate in silico reconstructions of canonical signaling and metabolic pathways plus regulatory control networks; (ii) in vivo and ex vivo quantitative measurements of myocardial fuel choice, energy utilization, and functional performance, using magnetic resonance spectroscopy of whole tissue, plus biochemical phenotyping of isolated mitochondria; (iii) microscopic analysis of cellular phenotypes, using histological and immunohistochemical methods; (iv) targeted and unbiased biochemical analysis (mass spectrometry) of biospecimens; and (v) non-invasive hemodynamic assessment (mouse echocardiography) to characterize in vivo the cardiac structural and functional responses to nutritional, genetic, and ischemic states. To dissect molecular mechanisms of metabolic control via gain- (e.g., adenoviral transduction/over-expression) and loss- (e.g., RNAi) of-function, we deploy myocardial model cell culture systems. Lastly, we are actively engaged in projects that determine the relationship among nutrient-metabolite delivery, utilization, and the pathogenesis of cardiomyopathy in the human heart.
Selected Publications:
Crawford PA, Crowley JR, Sambandam N, Muegge BD, Costello EK, Hamady M, Knight R, Gordon JI. Regulation of myocardial ketone body metabolism by the gut microbiota during nutrient deprivation. Proc Natl Acad Sci U S A. 2009 106:11276-11281 B.
Bäckhed F and Crawford PA. Coordinated regulation of the metabolome and lipidome at the host-microbial interface. BBA Mol Cell Biol Lipids. 2009 Epub ahead of print.
Bäckhed F, Crawford PA, O’Donnell D and Gordon JI. Postnatal lymphatic partitioning from the blood vasculature in the small intestine requires fasting-induced adipose factor. Proc Natl Acad Sci U S A. 2007 104:606-611.
Crawford PA and Gordon JI. Microbial regulation of intestinal radiosensitivity. Proc. Natl. Acad. Sci. U.S.A. 2005 102: 13254-13259.
Crawford PA, Dorn C, Sadovsky Y, Milbrandt J. (1998) Nuclear receptor DAX-1 recruits nuclear receptor corepressor N-CoR to steroidogenic factor 1. Mol Cell Biol. 1998 18: 2949-56.
Last Updated: 10/19/2009 |