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
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.
Credentials & Experience
Education & Training
- MD, PhD, Pharmacology, Medicine, New York Univ School of Medicine
- Internship: Bellevue & New York University Medical Center, NY
- Residency: Neurological Institute of the Columbia-Presbyterian Hospital
- Fellowship: Columbia College of Physicians & Surgeons
Our laboratory studies the molecular mechanisms of neuronal degeneration and death, particularly the regulation of caspase activity. Neuronal degeneration and death are the hallmarks of many neurological diseases, including Alzheimer’s Disease, Parkinson’s Disease and stroke, and there is considerable evidence that caspases play a critical role in the progression of these diseases. We have been studying the molecular mechanisms of neuronal death in cultured primary neurons for many years, using various pathologically relevant death stimuli, including beta-amyloid and trophic factor deprivation and have more recently begun studying in vivo rodent models of neuronal dysfunction and dysregulation of the neurovascular unit. The rodent stroke model provides an excellent system to move our molecular studies in vivo. This model provides reproducible edema and neuronal death and is also a model of a major human health concern. We are also modeling retinal edema using a mouse model of retinal vein occlusion. Our studies in primary neurons have found that different death pathways are initiated by different death stimuli; this is very important from both a mechanistic and a therapeutic standpoint as it provides for the possibility of specific interventions that abrogate the aberrant death signaling but do not interfere with the normal death pathways that are necessary for normal function of the organism. To study death pathways we have developed molecular tools that allow the study of individual members of protein families. Current work also includes mouse with cell specific deletion of individual caspases to determine the cell specific functions of these proteins in the adult nervous system.
Ongoing projects in the laboratory include:
Determining the cell specific functions of caspase-9 in regulation of blood brain barrier integrity
Determining the cellular mechanisms regulating retinal edema utilizing a mouse model of retinal vein occlusion
Caspase function in axonal maintenance
Determination of the activation complex of caspase-2. Caspase-2 is a critical regulator of neuronal death.
Determining the role of caspase-2 in normal cognitive development
Beta-amyloid regulation of caspase-IAP complexes in neurons and synapses.
Determination of the spatial, temporal and cell-type activation of caspases during stroke.
Establishing therapeutic windows of intervention for stroke. These windows are based on the underlying mechanisms of cell dysfunction and death over the course of stroke.
- Neural Degeneration and Repair
- Neurobiology of Disease
- Regulation of the neurovascular unit
GENERATION OF CASPASE-9 CELL SPECIFIC INDUCIBLE KNOCKOUT MICE FOR THE STUDY OF MECHANISMS OF CEREBRAL EDEMA (Federal Gov)
Feb 1 2017 - Jan 31 2019
KAIROS VENTURES (Private)
Jul 3 2017 - Jun 30 2018
MECHANISMS AND TREATMENT OF CNS EDEMA (Federal Gov)
Jul 1 2013 - Jun 30 2018
MECHANISMS OF NEURONAL DEATH FOLLOWING TBI (Sponsored Government Other)
Jun 1 2014 - May 31 2017
IN VIVO RETINAL IMAGING TO ASSESS MECHANISMS OF AXONAL MAINTENANCE (Federal Gov)
Aug 1 2014 - Jul 31 2015
A NOVEL THERAPEUTIC FOR DIABETIC MACULAR EDEM (Private)
Feb 8 2013 - Feb 7 2015
CELL-SPECIFIC TARGETS AND FUNCTIONS OF CASPASE-9 IN CEREBRAL ISCHEMIA (Federal Gov)
Jul 1 2014 - Sep 13 2014
DOWNSTREAM REGULATORS OF BETA-AMYLOID INDUCED NEURONAL DEATH (Federal Gov)
Dec 1 2000 - Jul 31 2011
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.
Jean YY, Ribe EM, Pero ME, Moskalenko M*, Iqbal Z*, Marks LJ*, Greene LA and Troy CM. (2013) Caspase-2 is essential for c-Jun transcriptional activation and Bim induction in neuron death. Biochem J.;455(1):15-25.
Pozueto J, Lefort R, Ribe EM, Troy CM, Arancio O, Shelanski M. (2013) Caspase-2 is required for dendritic spine and behavioural alterations in J20 APP transgenic mice. Nat Commun. 4:1939. doi: 10.1038/ncomms2927.
Ribe EM, Jean YY, Goldstein, RL*, Manzl, C, Stefanis, L, Villunger, A, and Troy, CM. (2012) Neuronal caspase-2 activity and function requires RAIDD, but not PIDD. Biochem J. 444, 591-599.
Tamayev R, Akpan N, ArancioO, Troy CM, D'Adamio L. (2012) “Caspase-9 mediates synaptic plasticity and memory deficits of Danish dementia knock-in mice: caspase-9 inhibition provides therapeutic protection.” Mol Neurodegener. 10.1186/1750-1326-7-60.
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., 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. 31:8894-8904.
Puzzo, D., Privitera, L., Fa’, M., Staniszewski, A., Hashimoto, G., Aziz, F., Sakurai, M., Ribe, E. M., Troy, C. M., Mercken, M., Jung, S. S., Palmeri, A. and Arancio, O. (2011) “Endogenous amyloid-β is necessary for hippocampal synaptic plasticity and memory” Ann. Neurol. 69:819-30.
Troy, C. M., Akpan, N. and Jean, Y.Y. (2011) “Regulation of Caspases in the Nervous System: Implications for functions in health and disease” Proteases in Health and Disease, ed. E. Di Cera Prog Mol Biol Transl Sci. 99C:265-305.
Ribe Garrido, E, Heidt, L*, Beaubier, N and Troy C. M. (2011) “Molecular Mechanisms of Neuronal Death” Advances in Neurobiology, vol 1, Neurochemical Mechanisms of Disease ed. Blass, JP, pages 17-48.
Siddiq A, Aminova LR, Troy CM, Suh K, Messer Z, Semenza GL, Ratan RR. (2009) Selective inhibition of hypoxia-inducible factor (HIF) prolyl-hydroxylase 1 mediates neuroprotection against normoxic oxidative death via HIF- and CREB-independent pathways. J Neurosci. Jul 8;29(27):8828-38.
Ho CC, Rideout HJ, Ribe E, Troy CM, Dauer WT. (2009) The Parkinson disease protein leucine-rich repeat kinase 2 transduces death signals via Fas-associated protein with death domain and caspase-8 in a cellular model of neurodegeneration. J Neurosci. Jan 28;29(4):1011-6.
Troy CM, Ribe EM. (2008) Caspase-2: vestigial remnant or master regulator? Sci Signal. Sep 23;1(38):pe42.
Ribe EM, Serrano-Saiz E, Akpan N, Troy CM. (2008) Mechanisms of neuronal death in disease: defining the models and the players. Biochem J. Oct 15;415(2):165-82. Review.
Biswas SC, Shi Y, Vonsattel JP, Leung CL, Troy CM, Greene LA. (2007) Bim is elevated in Alzheimer's disease neurons and is required for beta-amyloid-induced neuronal apoptosis. J Neurosci. Jan 24;27(4):893-900.
Greene LA, Liu DX, Troy CM, Biswas SC. (2007) Cell cycle molecules define a pathway required for neuron death in development and disease. Biochim Biophys Acta. Apr;1772(4):392-401. Epub 2006 Dec 13. Review.
Davidson, T. J., Harel, S., Arboleda, V. A., Shelanski, M. L., Greene, L. A. and Troy CM. (2004) Highly efficient siRNA delivery to primary mammalian neurons induces microRNA-like effects before mRNA degradation. J. Neurosci 24:10040-10046.