Dr. Itender Singh's research focuses on the vascular and inflammatory components of pathophysiological conditions such as Alzheimer's disease (AD), stroke and acute lung injury. Under physiological conditions, the vascular endothelium and pericytes lining the blood vessels regulate blood flow, host-defense and selective transport of macromolecules. All these processes are altered or hampered during the above mentioned pathological conditions. Dr. Singh investigates such processes and underlying mechanisms of vascular dysfunction and associated inflammation, particularly in transgenic mice and in vitro models of brain and lung diseases. The research uses confocal and multiphoton imaging, in vivo and in vitro gene knockdown, blood flow measurements, vascular permeability assays and analysis of animal behavior among various other techniques.
An intact and functional blood-brain barrier is crucial to neuronal health and survival. Conversely, impaired cerebral blood flow and blood-brain barrier dysfunction associated with accumulation of toxic macromolecules in the brain can result in inflammation and cognitive decline. Neurovascular dysfunction has been identified as an important component of neurodegenerative disease pathology and may contribute to the development of chronic neurodegeneration. Dr. Singh was instrumental in showing that presence of ApoE4, a genetic risk factor for AD, inflicts damage to brain pericytes and results in a Cyclophilin A mediated breakdown of blood-brain barrier. In an AD mouse model, he is currently studying how trace levels of copper can induce neurovascular inflammation and impair vascular clearance of amyloid-beta from brain. He is also involved in elucidating the role of VEGF in blood vessel formation and maintenance in aging, cerebral ischemia/hypoxia and pathological conditions.
Dr. Singh is also interested in development of therapeutic strategies for AD and stroke using novel variants of activated protein C, protein S and other small molecule compounds. His recent study reported in Journal of Clinical Investigation describes FPS-ZM1, a unique small molecule compound that inhibits the RAGE receptor on endothelial cells of brain microvessels. FPS-ZM1 not only blocks the entry of toxic amyloid protein into the brain but is small enough to pass through the restrictive blood-brain barrier into the brain parenchyma, where it reduces oxidative stress, NF-kappa B-BACE1 pathway mediated amyloid-beta production, pro-inflammatory cytokines and gliosis in AD mice.
Dr. Singh is investigating the molecular mechanisms critical for the development of pulmonary vascular inflammation in parallel. He discovered that thrombin binding to the PAR1 receptor induces TRPC6 channel mediated calcium influx, which results in endothelial barrier permeability via RhoA activation, the hallmark of tissue inflammation. He is currently studying the role of autophagy and mTOR in neutrophil infiltration and induction of pro-inflammatory mediators in acute lung injury models.

• Bell RD, Winkler EA, Singh I, Sagare AP, Deane R, Wu Z, Holtzman DM, Betsholtz C, Armulik A, Sallstrom J, Berk BC, Zlokovic BV. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature. 2012 May 24; 485(7399):512-6.
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• Deane R, Singh I, Sagare AP, Bell RD, Ross NT, Larue B, Love R, Perry S, Paquette N, Deane RJ, Thiyagarajan M, Zarcone T, Fritz G, Friedman AE, Miller BL, Zlokovic BV. A multimodal RAGE-specific inhibitor reduces amyloid ß-mediated brain disorder in a mouse model of Alzheimer disease. J Clin Invest. 2012 Apr 2; 122(4):1377-92.
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• Bell RD, Winkler EA, Sagare AP, Singh I, LaRue B, Deane R, Zlokovic BV. Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging. Neuron. 2010 Nov 4; 68(3):409-27.
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• Zhu D, Wang Y, Singh I, Bell RD, Deane R, Zhong Z, Sagare A, Winkler EA, Zlokovic BV. Protein S controls hypoxic/ischemic blood-brain barrier disruption through the TAM receptor Tyro3 and sphingosine 1-phosphate receptor. Blood. 2010 Jun 10; 115(23):4963-72.
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• Zhong Z, Ilieva H, Hallagan L, Bell R, Singh I, Paquette N, Thiyagarajan M, Deane R, Fernandez JA, Lane S, Zlokovic AB, Liu T, Griffin JH, Chow N, Castellino FJ, Stojanovic K, Cleveland DW, Zlokovic BV. Activated protein C therapy slows ALS-like disease in mice by transcriptionally inhibiting SOD1 in motor neurons and microglia cells. J Clin Invest. 2009 Nov; 119(11):3437-49.
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• Fernández JA, Heeb MJ, Xu X, Singh I, Zlokovic BV, Griffin JH. Species-specific anticoagulant and mitogenic activities of murine protein S. Haematologica. 2009 Dec; 94(12):1721-31.
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• Guo H, Singh I, Wang Y, Deane R, Barrett T, Fernández JA, Chow N, Griffin JH, Zlokovic BV. Neuroprotective activities of activated protein C mutant with reduced anticoagulant activity. Eur J Neurosci. 2009 Mar; 29(6):1119-30.
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• Guo H, Wang Y, Singh I, Liu D, Fernández JA, Griffin JH, Chow N, Zlokovic BV. Species-dependent neuroprotection by activated protein C mutants with reduced anticoagulant activity. J Neurochem. 2009 Apr; 109(1):116-24.
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• Bell RD, Deane R, Chow N, Long X, Sagare A, Singh I, Streb JW, Guo H, Rubio A, Van Nostrand W, Miano JM, Zlokovic BV. SRF and myocardin regulate LRP-mediated amyloid-beta clearance in brain vascular cells. Nat Cell Biol. 2009 Feb; 11(2):143-53.
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• Wang Y, Thiyagarajan M, Chow N, Singh I, Guo H, Davis TP, Zlokovic BV. Differential neuroprotection and risk for bleeding from activated protein C with varying degrees of anticoagulant activity. Stroke. 2009 May; 40(5):1864-9.
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• Singh I, Knezevic N, Ahmmed GU, Kini V, Malik AB, Mehta D. Galphaq-TRPC6-mediated Ca2+ entry induces RhoA activation and resultant endothelial cell shape change in response to thrombin. J Biol Chem. 2007 Mar 16; 282(11):7833-43.
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