Carol M. Troy, MD, PhD

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

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

  • Avrutsky, M.I., Chen, C.W., Lawson, J.M., Snipas, S.J., Salvesen, G.S., and Troy, C.M. (2023). Caspase-9 inhibition confers stronger neuronal and vascular protection compared to VEGF neutralization in a mouse model of retinal vein occlusion. Frontiers in Neuroscience 17. 10.3389/fnins.2023.1209527.
  • Slavi, N., Balasubramanian, R., Lee, M.A., Liapin, M., Rachel Oaks-Leaf, R., Peregrin, J., Potenski, A.M., Troy, C.M., Ross, M.E., Herrera, E., Kosmidis, S., John, S.W.M., Mason, C.A. “CyclinD2-mediated regulation of neurogenic output from the retinal ciliary margin is perturbed in albinism”. https://doi.org/10.1016/j.neuron.2022.10.025
  • Bosc E, Anastasie J, Soualmia F, Coric P, Kim JY, Wang LQ, Lacin G, Zhao K, Patel R, Duplus E, Tixador P, Sproul AA, Brugg B, Reboud-Ravaux M, Troy CM, Shelanski ML, Bouaziz S, Karin M, El Amri C, Jacotot ED. Genuine selective caspase-2 inhibition with new irreversible small peptidomimetics. Cell Death Dis. 2022;13(11):959. Epub 20221115. doi: 10.1038/s41419-022-05396-2. PubMed PMID: 36379916; PMCID: PMC9666555.
  • Colon Ortiz, C., Neal, A.M., Avrutsky, M.I., Choi, M., Smart, J., Lawson, J., Troy, C.M. (2022). “Neurovascular injury associated non-apoptotic endothelial caspase-9 and astroglial caspase-9 mediate inflammation and contrast sensitivity decline”. Cell Death and Disease (2022) 13:937; https://doi.org/10.1038/s41419-022-05387-3.
  • Avrutsky, M. I. and Troy, C. M. (2021) “Caspase-9: a multimodal therapeutic target with diverse cellular expression in human disease" Frontiers in Pharmacology 2021;12:701301. Epub 2021/07/27. doi: 10.3389/fphar.2021.701301. PubMed PMID: 34305609; PMCID: PMC82990543
  • 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. PubMed PMID: 3257682
  • Troy, C.M. and Shelanski, M.L. (2016) "Caspase-2 and tau: a toxic partnership?", Nature Medicine, 22:1207-1208.
  • 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
  • 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. (Featured publication)
  • 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.(Featured in Faculty of 1000)