The aim of the Systems Biology Center is to create integrated models of complex biological processes and test them across the entire cellular and physiological network of interactions. Using high-throughput screening tools from the genomic, proteomic, and imaging arenas, coupled with powerful computing and modeling tools to integrate acquired data, Center investigators can examine gene and protein expression, enzyme activity, or other biological processes in a spatial and temporal context. Researchers in the Systems Biology Center are interested in diverse systems, such as cardiac disease, oxidative stress, cellular differentiation and memory, cell energetics and metabolism, and kidney function. This basic research helps fuel scientific discovery that may one day help advance research related to heart, lung, blood, and sleep conditions or other fields.
Creating energy is an inherently dangerous process requiring careful monitoring and quick eradication of damaging byproducts. Cells therefore have mitochondrial function under tight regulatory control. Since his discovery some years ago that mitochondria in the heart can supply energy at a rate that perfectly matches a range of physiological demands, Dr. Robert Balaban, who leads the Laboratory of Cardiac Energetics, has sought to understand how mitochondria are regulated to ensure this metabolic homeostasis. As a serendipitous offshoot of their efforts in non-linear microscopy, Dr. Balaban and his colleagues discovered that they could visualize the composition of blood vessel walls without the need for dyes. They are using this method to study the early stages of atherosclerosis. Based on the evidence they have obtained, Dr. Balaban is testing the hypothesis that atherosclerotic lesion formation is dependent upon the extracellular matrix composition of the vascular wall.
To study epigenetic mechanisms of development and differentiation across the mammalian genome, the Laboratory of Epigenome Biology, led by Dr. Keji Zhao, wanted a comprehensive and unbiased approach that would avoid the selection bias inherent in synthesizing probes for DNA microarrays. He and his colleagues therefore developed novel sequencing-based methods to study the epigenome, such as ChIP-Seq, which combines chromatin immunoprecipitation (ChIP) with the Next Generation Sequencing technique, and micrococcal nuclease sequencing (MNase-Seq). In addition, the team developed accompanying computational strategies to analyze the wealth of resulting sequence data. These tools are now widely applied in laboratories around the world.
Research in the Epithelial Systems Biology Laboratory, led by Dr. Mark A. Knepper, concentrates on the physiology and pathophysiology of the kidney, with particular focus on regulation of water and salt transport by the peptide hormone vasopressin. Maintaining the right balance of water and electrolytes in the body is a matter of life and death, so it is not surprising that several physiological mechanisms have evolved to regulate water retention and excretion. Disruption of any one of these mechanisms can lead to severe water balance disorders. Using a systems approach, Dr. Knepper is applying comprehensive proteomics, next-generation DNA sequencing, and computational approaches to understand the physiological principles and molecular mechanisms that control how the kidney excretes water and salt.
The Laboratory of Molecular Genetics, led by Dr. Hong Xu, is pioneering mitochondrial genetics and inheritance research in the fruit fly model (Drosophila melanogaster). For example, this lab has created a genetic approach to select for inheritable mitochondria DNA (mtDNA) mutations in flies, which paved a way to tackle several of the most important but unresolved issues concerning mtDNA genetics and diseases. This lab has uncovered a novel selective inheritance mechanism that limits the transmission of harmful mtDNA mutations in female germline. Dr. Xu’s lab is exploring the cellular processes and principles guiding mtDNA segregation and inheritance. His lab is also investigating how mtDNA mutations contribute to complex physiological traits and pathological conditions, such as aging and age-related disorders.
The focus of the Muscle Energetics Laboratory, led by Dr. Brian Glancy, is to determine how mitochondria are optimized within muscle cells to help maintain energy homeostasis during the large change in energy demand caused by muscle contraction. Particularly, his work aims to answer four broad questions: 1) how is mitochondrial energy conversion acutely up-regulated to meet energetic demand during a bout of muscle contractions?; 2) what chronic mitochondrial adaptations are available to the muscle cell to improve the capacity for matching energy supply with demand?; 3) how does each chronic adaptation, or combinations thereof, alter the capacity for acute up-regulation of mitochondrial conversion?; and 4) how do acute mismatches between mitochondrial energy conversion and cellular energy demand signal chronic mitochondrial adaptations in skeletal muscle?
Genome technology has gradually become the major driving force for precision medicine and biomedical research. With the advent of single cell sequencing and single molecule sequencing, it is possible to tackle complex biological systems at an unprecedented molecular resolution. The Genome Technology program, led by Dr. Jun Zhu, is focused on the development of innovative genomic technologies, leveraging the latest advances in high-throughput genomics and computational tools, to facilitate collaborative and transformative research at the NHLBI DIR. Specifically, the aim is to improve single cell transcriptomic/epigenetic analysis, and cell-free DNA/RNA profiling using liquid biopsy.
The Renal Cellular and Molecular Biology Section is led by Dr. Maurice Burg, a renal physiologist who has made seminal and significant contributions to the field in two major areas. First, he invented a method to dissect viable renal tubules and perfuse them in vitro, measuring transport of substances between the tubule lumen and peritubular side. Using this method, he and others have determined what is transported by each of the many different nephron segments, how it is transported, and how the transport is regulated. This information has been fundamental for our current understanding of how the kidney functions in health and disease. Second, his lab is currently investigating the mechanisms by which kidney cells protect themselves from the very high renal medullary interstitial concentrations of salt and urea that power concentration of the urine.
Sleep is an enduring biological puzzle in that it appears to lack an adaptive advantage; a sleeping animal cannot forage for food, mate, or defend itself against predation. Yet, as every long-distance traveler, insomniac, or parent of a colicky infant knows, sleep deprivation is detrimental to health and cognition. Sleep is a complex trait, meaning it varies among individuals and influenced by many genes. Sleep is also sensitive to multiple environmental factors, making it hard to assess the effect of a single gene in all potential environmental conditions and genetic backgrounds in human populations. In the Laboratory of Systems Genetics, led by Dr. Susan T. Harbison, research is currently focused on her interest in complex traits—and the use of genomic technologies to study them—to solve this challenging problem.