overview
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Dr. Steven Carroll is is Professor and Chair of the Department of Pathology and Laboratory Medicine at the Medical University of South Carolina (MUSC), where he holds the Gordon R. Hennigar, Jr., MD, Endowed Chair in Pathology. Dr. Carroll is board certified by the American Board of Pathology in Anatomic Pathology and Neuropathology. Dr. Carroll’s research program, which is funded by the National Institutes of Health, the Department of Defense and the Children’s Tumor Foundation, studies the role that the growth factor neuregulin-1 and its erbB receptors plays in the pathogenesis of neurodegenerative diseases and neurofibromatosis-associated peripheral nerve sheath tumors.
Dr. Carroll serves as the Director of the South Carolina Alzheimer’s Disease Research Center at MUSC and as Director of the Carroll A. Campbell Jr. Neuropathology Laboratory (Brain Bank). Dr. Carroll also serves as Director of the Hollings Cancer Center Biorepository & Tissue Analysis Shared Resource. Dr. Carroll is an Associate Editor for the American Journal of Pathology and the Journal of Neuropathology and Experimental Neurology and is a member of the Editorial Board for Neuro-Oncology. He is a founding member of the international Down Syndrome Biobanking Consortium, which includes MUSC, the Barrow Neurological Institute, the University of Colorado Denver, the University of California Irvine, New York University, the Sant Pau Memory Unit (Barcelona, Spain), Cambridge University (UK), the Karolinska Institutet (Stockholm, Sweden) and the University of Calcutta (India). Working with the Children’s Tumor Foundation, Dr. Carroll has established a national network to bank biospecimens from autopsied patients who had neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2) and schwannomatosis. In addition to these research areas, Dr. Carroll participates in the Human Cooperative Tissue Network, a multi-institution network that banks and distributes tumor tissue for research to investigators across the United States and elsewhere. The Biorepository is also an active participant in an effort headed by Dr. Marvella Ford that partners MUSC with South Carolina State University; this project focuses on understanding the basis for disparate outcomes in cancer patients from diverse backgrounds.
Dr. Carroll received his B.S. degree from the University of Memphis in 1981. He then attended Baylor College of Medicine, receiving his Ph.D. in Cell Biology in 1986 and his M.D. in 1988. Dr. Carroll’s postdoctoral research fellowship, Anatomic Pathology Residency and Neuropathology Fellowship were performed at the Washington University School of Medicine (1988-1994). Prior to his arrival at MUSC, Dr. Carroll was Professor of Pathology, Neurobiology and Cell Biology at the University of Alabama at Birmingham (UAB) and the Director of the UAB Division of Neuropathology. While at UAB, Dr. Carroll served as an attending neuropathologist at the University of Alabama Hospital, the Birmingham VA, UAB Highlands Hospital and Alabama Children’s Hospital. He was a Scientist in the UAB Alzheimer’s Disease Research Center, the Mental Retardation Research Center, the Center for Aging, the Center for Glial Biology in Medicine, the Civitan International Research Center and the Center for Neurodegeneration and Experimental Therapeutics as well as being as a Member of the Comprehensive Neuroscience Center and a Senior Scientist in the UAB Comprehensive Cancer Center. Dr. Carroll is certified by the American Board of Pathology in Anatomic Pathology and Neuropathology.
The Carroll laboratory focuses on identifying the abnormalities that promote the pathogenesis of cancer and neurodegenerative diseases and using this information to develop effective new therapies. We have a particular interest in the role that the growth factor neuregulin-1 (NRG1) and its erbB receptors play in the development of these diseases.
Our work in cancer biology is directed towards determining how neurofibromas and malignant peripheral nerve sheath tumors (MPNSTs) develop in patients with the multi-system genetic disease neurofibromatosis type 1 (NF1) with therapeutic development being the end goal. We are pursuing a two-pronged approach to achieve this goal. In our first approach, we are using our understanding of the natural history of neurofibromas and MPNSTs to guide us to existing agents that are potentially effective against these tumors. For instance, since aberrant Ras signaling is characteristic of these tumors, we have used phosphoproteomics and other approaches to identify potential druggable targets within the pathways downstream of NF1-regulated Ras proteins as well as upstream activators of Ras in neurofibromas and MPNSTs. This latter group includes receptors for the growth factor neuregulin-1 (NRG1), which led us to create mice in which we can genetically ablate these receptors and examine the effect this has on MPNST pathogenesis. Our second, longer term approach is to identify novel therapeutic targets by comprehensively defining the genomic and epigenetic abnormalities that mediate the pathogenesis of plexiform neurofibromas and MPNSTs. To achieve this, we are using cross-species comparative oncogenomics, a method in which driver mutations are first identified in a mouse cancer model and then validated in human tumors. For these studies, we have created several genetically engineered mouse models which recapitulate the process of neurofibroma-MPNST progression seen in humans. We have performed comprehensive genomic analyses (array comparative genomic hybridization, high density SNP array analyses, whole exome sequencing and whole transcriptome sequencing) of MPNSTs from these mice, together with a reference set of human MPNST tumors and cell lines, to identify the driver mutations responsible for tumor development. We have partnered these genomic analyses with functional (genome-scale shRNA) screens to identify gene products that are essential for proliferation and survival. Ongoing work is directed towards performing preclinical trials with mouse models to test the effectiveness of drugs that target these gene products.
Our work in neurobiology focuses on Alzheimer’s disease, frontotemporal dementias and amyotrophic lateral sclerosis (ALS). Our laboratory was the first to show that NRG1, a protein that plays an important role in synaptogenesis, and its receptors are aberrantly distributed in neuritic plaques in humans with Alzheimer’s disease and genetically engineered mouse models of Alzheimer’s disease. After globally identifying the cellular populations expressing erbB receptors in the adult rat brain with immunohistochemistry and in situ hybridization, we additionally showed that NRG1 plays an important role in shaping the dendritic and axonal trees of hippocampal neurons and that this growth factor is an important survival factor for motor neurons in the spinal cord. At present, we are constructing several new genetically engineered mouse models to assess the role that specific erbB mutations play in the pathogenesis of frontotemporal dementias and ALS and to ascertain whether NRG1 can be used to slow the development of Alzheimer’s disease and other dementias.
As with our cancer work, we partner mouse and cell culture models of neurodegenerative diseases with studies of brain tissue and other biospecimens collected from patients with dementia. These studies are facilitated by the fact that Dr. Carroll is the Director of the Carroll A. Campbell, Jr. Neuropathology Laboratory, which contains a collection of several hundred brains from patients with Alzheimer’s and related dementias that have been donated for research. In collaboration with Drs. Eric Hamlett, Brad Schulte and Judy Dubno, we are using these specimens to determine whether pathologic changes affecting the brain circuitry responsible for hearing and other senses occurs in Alzheimer’s disease and whether clinical changes in these senses can be used as a biomarker for diagnosing the early stages of Alzheimer’s disease. As noted above, the Carroll A. Campbell, Jr. Neuropathology Laboratory is a founding member of an international consortium of brain banks that collect brain tissue and other research specimens from Down syndrome patients, who almost inevitably develop Alzheimer’s disease in their forties. In collaboration with Dr. Eric Hamlett and Lotta Granholm, we have used specimens from these patients to establish that changes in the protein cargo contained in neuronally-derived exosomes can be used as a biomarker for the early stages in the development of Alzheimer’s disease.
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