Carol M. Troy, MD, PhD
- Associate Professor of Pathology and Cell Biology and Neurology (in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain) at CUMC
My laboratory asks the question how do neurons die. Our work aims to determine the molecular mechanisms of neuronal dysfunction and death to understand the death process and identify targets for therapeutic intervention. We are specifically investigating the regulation and function of caspases, the family of cell death proteases. In our work we utilize in vitro and in vivo models of acute and chronic neurodegeneration to model cerebral ischemia, Alzheimers Disease and diabetic macular edema. We utilize imaging, molecular, and biochemical approaches to understand the neuronal death mechanisms. We have been at the forefront of establishing non-toxic methods to introduce DNA, RNA and peptides into neurons to use as molecular dissection tools to identify pathways and ultimately as therapeutic interventions. Our work has shown that in neurons the death stimulus determines which caspase pathways are critical in the execution of death. Our recent work in rodent models of cerebral ischemia suggests that caspases are active early in stroke, and that inhibition of caspase-9 activity provides substantial cellular and functional neuroprotection, abrogating the development of axonal and neuronal loss and of edema. We have also identified caspase-2 as a target in AD, as caspase-2 is required for synapse loss and neuron death in models of AD. Our current approaches are to develop specific inhibitors of activity of individual caspases to selectively abrogate aberrant pathways with minimal toxicity or side effects.
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 death. The rodent stroke model provides an excellent system to move our molecular studies in vivo. This model provides reproducible neuronal death and is also a model of a major human health concern. 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.
Ongoing projects in the laboratory include:
- Determination of the activation complex of caspase-2. Caspase-2 is a critical regulator of neuronal death.
- Identification and characterization of targets of caspase-2 in neuronal death.
- Studies of the mechanism of caspase-mediated regulation of Bim during beta-amyloid mediated death
- Dose-dependent effects of beta-amyloid on spine density in hippocampal neurons. These studies encompass the physiologic and pathophysiologic functions of beta-amyloid.
- Beta-amyloid regulation of caspase-IAP complexes in neurons and synapses.
- Development and characterization of an in vivo model of beta-amyloid-mediated neuronal death
- Studies of the function of caspase-6 in stroke.
- 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.
- Department of Pathology & Cell Biology
- Department of Neurology
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
- Taub Institute for Research on Alzheimer's Disease and the Aging Brain
William Black Building650 West 168th Street
New York, NY 10032
- (212) 305-3119
- Neural Degeneration and Repair
- Neurobiology of Disease
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
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
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.