Research Interests:  Skeletal development and aging, osteoarthritis, role of senescent cells in skeletal aging, mechano-transduction

We study molecular mechanisms of cell aging and senescence that lead to skeletal system degenerative diseases in humans. Specifically, we use the osteoarthritic joint cartilage as our model system to analyze how senescence-associated cell transitions and interactions result in tissue pathology.

Biological consequences of DNA damage, inflammation, oxidative stress

Our research aims to unravel the connections between DNA damage and disease. Using the methods and tools of biochemistry, synthetic chemistry, molecular biology, toxicology and biophysics we probe the effects of DNA damage from the molecular to the cellular level. As a chemistry lab, we exploit our abilities to synthesize DNA lesions and study their properties within well-defined systems. For instance, we are interested in determining the type and frequency of mutations caused by individual DNA lesions. Another focus of the lab is on understanding how chemically modifying DNA affects its overall structure and how those modifications influence the inheritance of genetic information.

Our lab has two major interests. Duchenne muscular dystrophy strikes one in 3,000 boys. Our basic research led to the discovery that the extracellular protein biglycan regulates an intrinsic cellular pathway that can compensate for the genetic defect in Duchenne.  We are currently developing recombinant biglycan as a therapeutic for Duchenne.  Biglycan also holds promise as a therapy for ALS and Congenital Muscular Dystrophy.  

Second, how do we learn, and why are we so good at it when we are young? Using Fragile X mental retardation as a model, we seek to understand how ephemeral episodes of experience are transformed into stable changes in synaptic architecture and efficacy.  We are particularly interested in how local RNA translation in axons shapes brain circuitry and function.

Reproductive aging and senescence, chromatin and transcriptional control, tissue specific gene expression in the mouse reproductive system

Dr. Freiman's laboratory is interested in deciphering mechanisms of gene expression patterns critical for proper organ development and function in mammals. The lab primarily uses gene targeting in the mouse as a genetic tool to perturb the normal function of gene regulatory proteins in mammalian development. As an application of their research, these researchers aim to understand how the disruption of normal gene expression networks may affect the etiology of disease states in humans, such as infertility and ovarian cancer.

Genetic control of longevity, calorie restriction, Sir2, resveratrol, Drosophila model system

Stephen Helfand is recognized for his research on the molecular mechanisms underlying the process of aging, as well as the metabolic changes that occur with and contribute to the deleterious aspects of aging. His group began studying the molecular genetics of aging using Drosophila in 1992. Their initial work was directed at understanding the relationship between gene regulation and aging, and led to the discovery of one of the first longevity genes, Indy. Studying Indy led to an interest in mitochondrial physiology and metabolism, and in the mechanisms underlying life span extension by dietary restriction. In these studies they discovered the life span-extending effects of the histone deacetylases Rpd3 and Sir2, and of resveratrol, a small molecule activator of Sir2. More recently, his lab has explored the role of chromatin remodeling on gene expression during aging. This research led to their discovery of the relationship between the activity of retrotransposable elements and the deleterious phenotypes of aging. His research has consistently used the tools of Drosphila molecular genetics, high-throughput genome-wide approaches and bioinformatics.

Cardiac arrhythmia, sudden death, heart aging

Gideon Koren's research focuses on the regulation of expression voltage-gated potassium channels and mechanisms of sudden death. One of his current research projects involves rabbits expressing dominant negative transgenes that suppress the expression of repolarization currents in the heart. Transmitters are implanted to monitor the heart rhythm to help determine when and why they might die of ventricular arrhythmias. In addition, Koren's group is studying the transcriptional regulation and trafficking of these channels.

Computational biology, bioinformatics, gene networks, and chromatin.

Dr. Kreiling’s research is focused on understanding the connection between age-associated changes in the epigenetic signature of chromatin and the resulting changes in gene expression. Aging is the primary risk factor for the onset of multiple degenerative conditions, such as dementias, cardiovascular diseases, diabetes and cancer, that are responsible for considerable morbidity and mortality.  Many of these disorders result from, at least in part, epigenetic changes and the accumulation of DNA damage that lead to genome instability over time. Ultimately, understanding the mechanisms in which age-associated changes in chromatin structure result in the development of aging phenotypes may lead to therapeutic interventions that extend both healthspan and lifespan.

X-chromosome inactivation, epigenetics, chromatin, Drosophila model system

Coordinate gene regulation is a fundamental process essential to all cells from the germ line to the immune system. Our long-term goal is to define how genes are identified for coordinate regulation, the key initial step in their regulation. Dosage compensation is one of the best model systems for studying this process because all of the genes on a single chromosome are specifically identified and co-regulated. Drosophila, like mammals, increase the transcript levels of a large number of diversely regulated genes along the length of the single male X-chromosome precisely two-fold relative to each female X-chromosome. We are developing innovative approaches to understanding how dosage compensation in Drosophila is established, the critical first step in coordinate regulation. By combining genetic, biochemical, and genomic approaches, we will address the following key overall question: How are global and gene-specific transcriptional regulatory signals integrated to precisely regulate genes?

Computational biology, bioinformatics, gene networks, chromatin

Dr. Neretti was formally trained in physics and has been working on interdisciplinary projects, which involve signal/image processing, and modeling of biological systems. His current focus is the application of high throughput techniques such as gene expression microarrays to study changes in the transcriptional network caused by genetic and environmental interventions that extend life span in model organisms. His most recent work includes the development of computational methods to detect age-associated chromatin changes in ChIP-chip and ChIP-seqexperiments.https://www.brown.edu/centers/biology-aging/node/56/edit?destination=admin/content/manage/people#

Molecular evolution, evolution of mitochondrial genomes, oxidative respiration

Professor David Rand is interested in how natural selection acts on genes and genomes. One major focus of his research is how the mitochondrial genome and its interactions with the nuclear genome influence animal performance, evolutionary fitness, and aging. A second major interest is how thermal selection influences the genetic composition of populations. The goals of this work are to identify the genetic interactions that allow organisms to adapt to environmental heterogeneity.

Evolution of brain function and behavior, neurodegeneration, RNA editing, ncRNAs, chromatin, Parkinson's disease

Dr. Reenan is an international leader in the area of eukaryotic gene regulation, and his laboratory has played a seminal role in understanding the process of RNA editing. His multidisciplinary approaches have spanned cutting-edge genetics and molecular biology, comparative genomics, computer modeling, and biophysical techniques in order to bring to light the biological importance of ancient and conserved regulatory processes. The Reenan lab's work has been funded by NIH, NSF, Ellison Medical Research Foundation, the CART fund for Alzheimer's Research, and the Cambridge Templeton Consortium's Emergence of Biological Complexity program. In the past few years Dr. Reenan has published research in journals such as Science, Nature, Cell, Neuron, and Nature Structural and Molecular Biology, as well as being highlighted in several of these journals in mini-reviews or "editor's choice" articles. Dr. Reenan's work was one of twelve groups highlighted in the FY2005 Budgetary Request to Congress by NIH-NIGMS.

Cell cycle control, cellular senescence, telomeres, epigenetics

John Sedivy is recognized for his efforts in mammalian genetics, having developed and pioneered in the late 1980's methods for gene targeting of somatic cells. In 1995 his lab isolated the first viable knockout of c-Myc in a rat fibroblast cell line, which led to his career-long interest in this important oncogene. Recently his group showed that mice with reduced Myc expression have increased longevity and improved health span. In 1997 his lab was the first to achieve a homozygous gene knockout in primary human cells, knocking out the CDKN1A gene (cyclin-dependent kinase inhibitor p21), and showing that this was sufficient to bypass cellular senescence. In 2004 his group developed a reliable single-cell biomarker of telomere-initiated senescence and delineated the signaling pathway between dysfunctional telomeres and the cell cycle. In 2006 they published the first in vivo quantification of cellular senescence in aging primates. More recently the Sedivy lab has been studying chromatin changes during cellular senescence, and though these investigations discovered the activation of retrotransposable elements in aging.

Demography, evolution and genetics of aging, endocrine control of longevity, insulin/IGF signaling, innate immunity, Drosophila model system

Dr. Tatar is widely recognized for key studies to understand the mechanisms of longevity control through the explicit analysis of age-specific mortality. Trained as an ecologist, Dr. Tatar initially worked on many natural species from beetles, to butterflies, grasshoppers and baboons. Aiming to understand the mechanisms of aging, Dr. Tatar subsequently trained in Drosophila genetics and then established a group at Brown University with the fly as its model. His work has established benchmarks on the effects of insulin/IGF signaling on longevity. Endocrine signaling through lipid hormones is an additional focus of Dr. Tatar's group, which will increase understanding of the age-dependent decline of innate immunity, cardiac function, and reproduction. Dr. Tatar also leads a multi-site study that is mapping the genetic factors responsible for female reproductive aging in a nonhuman primate model system, the baboon. Dr. Tatar was the founding editor-in-chief of Aging Cell and thereafter served two years on the Board of Reviewing Editors at Science. Since joining Brown University in 1997, Dr. Tatar has been continuously funded by the National Institute on Aging. Dr. Tatar has received both a New Investigator and Senior Investigator Award from the Ellison Medical Foundation.

Stem cells, transcription factor networks, chromatin, Insulin/IGF/FOXO signaling

The focus of Ashley Webb’s research is to discover the mechanisms responsible for stem cell aging in mammals, and identify strategies to preserve neural stem cell function in the aged brain. As a postdoctoral fellow, she used genome-wide approaches to investigate how the pro-longevity transcription factor FOXO3 promotes neural stem cell homeostasis. She found that FOXO3 directly regulates a program of aging and longevity-associated genes in neural stem cells. In addition, she discovered that FOXO3 restrains neurogenesis by interacting with the master regulator of neurogenesis, ASCL1. Current and future projects in the Webb lab will build on the discovery of the FOXO3 “longevity network”, and address the question of how transcription factor networks and chromatin states affect the decline in neural stem cell function and neurogenesis with age. In the long term, understanding the molecular mechanisms that are required for neural stem cell homeostasis, neurogenesis, and maturation to functional neurons will better our understanding of why these processes decline with age, and ultimately how to treat aging-related and neurodegenerative disease pathologies.

DNA damage, oxidative stress, chromatin changes, WRN protein

DNA is the principal target of the vast majority of human carcinogens. These genotoxic chemicals initiate the carcinogenic process by causing DNA damage that subsequently generates mutations through erroneous replication. DNA is also the main target of several classes of chemotherapeutic drugs that exploit the vulnerability of cancer cells to certain forms of DNA damage. Our main research efforts are directed at the characterization of biochemical and genetic factors that regulate resistance to DNA damage-induced cell death and susceptibility to mutagenesis. DNA protein crosslinkingcan be caused by endogenous and exogenous aldehydes (formaldehyde, acetaldehyde and others. The biological role of DNA-protein crosslinks is poorly understood relative to smaller forms of DNA damage but these superbulky lesions are likely to act as potent inducers of large chromosomal rearrangements and cellular senescence. Induction of a senescent state in cancer cells will terminate tumor growth, whereas age-associated accumulation of senescence-promoting DNA-protein crosslinks can contribute to tissue aging.