Carol M. Troy, MD, PhD

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Overview
Credentials & Experience
Research

Overview

The work in my laboratory stems from my long-standing interest in understanding the molecular specificity of death pathways. Throughout the body there is homeostasis of life and death at the cellular level. In disease where death is dysregulated in particular cells there is alteration in the affected cells but not throughout the body. Thus we need to identify specific targets that are altered in the disease state but are not required for normal cellular homeostasis. In our lab we focus on the regulation and function of the caspase family of proteases in the mature nervous system. Best known as the executors of cell death, there is increasing appreciation that some caspases may also have non-apoptotic functions. Individual caspases cleave specific substrates at one or two cleavage sites. Cleavage can result in inactivation of a substrate, a change in the substrates activity, or target the substrate for ubiquitination and degradation. However, caspase cleavage of a substrate on its own does not degrade the cellular proteins. This positions aberrant caspase activity as a potential therapeutic target. We are utilizing novel approaches to inhibit specific family members to dissect the function of each in the normal nervous system and in disease. We utilize in vivo and in vitro models to study both molecular pathways and therapeutic interventions.
Email: cmt2@cumc.columbia.edu

Academic Appointments

Professor of Pathology and Cell Biology and Neurology (in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain) at CUMC

Gender

Female

Credentials & Experience

Education & Training

MD, PhD, 1984 Pharmacology, Medicine, New York Univ School of Medicine
Internship: 1985 Bellevue & New York University Medical Center, NY
Residency: 1988 Neurological Institute of the Columbia-Presbyterian Hospital
Fellowship: 1989 Columbia College of Physicians & Surgeons

Research

Our laboratory studies the molecular mechanisms of neuronal degeneration and death, particularly the regulation of caspase activity. A central question of our work is the function of the individual members of this multi-membered family in the nervous system. We seek to understand the cell-specific apoptotic and non-apoptotic signaling of the individual caspases in development and disease in the nervous system. We utilize mouse models and employ genetic and pharmacologic approaches to elucidate mechanisms.
We have identified non-apoptotic activation of endothelial caspase-9 as a critical mediator of edema, inflammation and cell death in a mouse model of retinal edema (Avrutsky et al., 2020). Prior work in our lab identified caspase-9 as the initial caspase activated in rodent models of cerebral ischemia. In all of these models there is neurovascular dysfunction and on-going studies are addressing how endothelial caspase-9 is signaling to the multiple cell types of the neurovascular unit, including microglia, astroctyes and neurons. Since there is often overlap of developmental pathways with those activated in disease we utilized the postnatal establishment of the mature retinal vasculature to examine potential developmental functions of endothelial caspases in vascular development and have found that endothelial caspase-8 plays a critical role in vessel outgrowth and pruning from postnatal days 6-10.
Current projects include 1) determining how endothelial caspase-9 regulates inflammation; 2) elucidating the critical substrates of endothelial caspase-9 in retinal edema; 3) establishing how endothelial caspase-8 regulates normal retinal angiogenesis; 4) developing and characterizing a mouse model of intracerebral hemorrhage using focused ultrasound and lipid microbubbles (in collaboration with the Konafagou lab); 5) determining the role of cradd, the death adaptor of caspase-2 in cognitive development.

Research Interests

Intellectual Disabilities
Neural Degeneration and Repair
Neurobiology of Disease
Regulation of the neurovascular unit

Selected Publications

Colón Ortiz C, Potenski A, Lawson JM, Smart J, Troy CM. Optimization of the Retinal Vein Occlusion Mouse Model to Limit Variability. J Vis Exp. 2021 Aug 6;(174). doi: 10.3791/62980. PubMed PMID: 34424250.
Avrutsky MI, Troy CM. Caspase-9: A Multimodal Therapeutic Target With Diverse Cellular Expression in Human Disease. Front Pharmacol. 2021;12:701301. Epub 2021/07/27. doi: 10.3389/fphar.2021.701301. PubMed PMID: 34305609; PMCID: PMC8299054.
Belarde, J.A., Chen, C.W., Rafikian, E. Yang, M., and Troy, C.M. (2021) “Optimizing touchscreen measures of rodent cognition by eliminating image bias” bioRxiv preprint doi: 10.1101/2021.04.05.438342.
Avrutsky, M.I., Colon Ortiz, C, Johnson, K.V., Potenski, A.M. Chen, C.W., Lawson, J.M., White, A.J., Yuen, S.K., Morales, F.M., Canepa, E., Snipas, S.J., Salvesen, G.S., Jean, Y.J., Troy, C.M. 2020. Endothelial activation of caspase-9 promotes neurovascular injury in retinal vein occlusion. Nature Communications DOI 10.1038/s41467-020-16902-5.
Montroull LE, Rothbard DE, Kanal HD, D'Mello V, Dodson V, Troy CM, Zanin JP, Levison SW, Friedman WJ. Proneurotrophins Induce Apoptotic Neuronal Death After Controlled Cortical Impact Injury in Adult Mice. ASN Neuro. 2020 Jan-Dec;12:1759091420930865.?
Di Donato, N., Ying Y. Jean,Y.J.,? A. Murat Maga,A., Krewson, B.D., Shupp, A.B.,Avrutsky, M.I., Roy, A., Collins, S., Olds, C., Willert, R.A., Czaja, A.M.,Johnson, R., Stover, J.A., Gottlieb, S., Bartholdi, D., Rauch, A., Goldstein, A., Boyd-Kyle, V., Aldinger, K.A., Mirzaa, G.M., Nissen, A., Brigatti, K.W., Puffenberger, E.G., Millen, K.J., Strauss, K.A., Dobyns, W.B.,Troy, C.M., and Jinks, R.N. (2016) “Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly with a Rare Lissencephaly Variant” AJHG 99: 1-13.?
Troy, C.M. and Shelanski, M.L. (2016) "Caspase-2 and tau: a toxic partnership?", Nature Medicine, 22:1207-1208.
Baleriola, J., Walker, C.A., Jean, Y.J., Crary, J.F., Troy, C.M., Nagy, P.L., and Hengst, U. (2014) Axonally synthesized ATF4 transmits a neurodegenerative signal across brain regions. Cell, 158:1159-1172.
Jean, Y.Y., Ribe, E.M., Pero, M.E., Moskalenko, M., Iqbal, Z., Marks, L.J., Greene, L.A., Troy, C.M. (2013). Caspase-2 is essential for c-Jun transcriptional activation and Bim induction in neuron death” Biochemical J. 455:15-25.
Ribe, E., Jean, Y.Y., Goldstein, R.L., Manzl, C., Stefanis, L. Villunger, A., Troy, C.M. (2012) RAIDD but not PIDD is essential for caspase-2 activity and function in neurons. Biochemical J. 444(3): 591-9.
Akpan, N., Serrano-Saiz, E., Zacharia, B.E., Otten, M.L., Ducruet, A.F., Snipas, S.J., Liu, W., Velloza, J., Cohen, G., Sosunov, S.A., Frey II, W.F., Salvesen, G.S., Connolly Jr, E.S., Troy, C.M. (2011) Intranasal delivery of caspase-9 inhibitor reduces caspase-6-dependent axon/neuron loss and improves neurological function after stroke. J Neurosci. 31:8894-904.
Davidson, T. J., Harel, S., Arboleda, V. A., Shelanski, M. L., Greene, L. A. and Troy, C. M. (2004) Highly efficient siRNA delivery to primary mammalian neurons induces microRNA-like effects before mRNA degradation J. Neurosci. 24:10040-10046.
Rabacchi SA, Friedman WJ, Shelanski ML, Troy CM. (2004) Divergence of the apoptotic pathways induced by 4-hydroxynonenal and amyloid beta-protein.? Neurobiol Aging 25(8):1057-1066.