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Position Title
Associate professor
Office Location
6135 Woodward Ave. – 3414 Integrative Bioscience Center (IBio)
Office Phone
313-577-5442
Biography
Research Educator, Full time, Ph.D
Vascular diseases are the leading cause of morbidity and mortality in developed societies, and my research focuses on understanding the molecular mechanisms of vascular diseases particularly atherosclerosis, restenosis, and proliferative retinopathies. The underlying pathogenesis in these vascular diseases is complex, and our general approach is to characterize these pathological responses at the molecular level, in cultured cells, and in the mouse models that mimic these specific types of vascular injury. Our research involves a multidisciplinary approach that includes various biochemical and cell biology procedures (Western blot analysis, 2-D gel electrophoresis, high-performance liquid chromatography, tube formation assay, cell migration assay, transfections, live cell imaging, confocal microscopy, immunoprecipitation, immunoblot analysis), molecular biology techniques (electrophoretic mobility shift assay, chromatin immunoprecipitation assay, site-directed mutagenesis, and cloning), and various animal models (Rat/mouse carotid artery injury, hind-limb ischemia, oxygen-induced retinopathy, and ApoE-/- mouse atherosclerotic model). Our ongoing studies involve defining the molecular bases for these pathologies and hope to find new targets for therapeutic intervention to improve vascular disease prevention and treatment.
Education
- Doctor of Veterinary Medicine (BVSc & AH), GBPUA&T, Pantnagar, India (1997 - 2002)
- Master of Veterinary Science (MVSc), ICAR-NDRI, Karnal, India (2002 - 2004)
- PhD, Animal Biochemistry, ICAR-NDRI, Karnal, India (2004 - 2008)
- Postdoctoral Fellow, University of Tennessee HSC, USA (2008-2010)
Selected publications
- Raghavan S, Singh NK, Gali S, Mani AM, Rao GN. Response by Raghavan et al to Letter Regarding Article, "Protein Kinase Cθ via Activating Transcription Factor 2-Mediated CD36 Expression and Foam Cell Formation of Ly6C(hi) Cells Contributes to Atherosclerosis". Circulation 139: 2079-2080, 2019. PMID: 31070938.
- Singh NK, Rao GN. Emerging role of 12/15-Lipoxygenase (ALOX15) in human pathologies. Prog Lipid Res. 73: 28-45, 2019. PMCID: PMC6338518.
- Raghavan S, Singh NK, Gali S, Mani AM, Rao GN. Protein Kinase Cθ Via Activating Transcription Factor 2-Mediated CD36 Expression and Foam Cell Formation of Ly6C(hi) Cells Contributes to Atherosclerosis. Circulation 138: 2395-2412, 2018. PMCID: PMC6309268.
- Singh NK, Janjanam J, Rao GN. p115 RhoGEF activates the Rac1 GTPase signaling cascade in MCP1 chemokine-induced vascular smooth muscle cell migration and proliferation. J Biol Chem. 292: 14080-14091, 2017. PMCID: PMC5572933.
- Singh NK, Kotla S, Kumar R, Rao GN. Cyclic AMP Response Element Binding Protein Mediates Pathological Retinal Neovascularization via Modulating DLL4-NOTCH1 Signaling. EBioMedicine 2: 1767-1784, 2015. PMCID: PMC4740322.
- Singh NK, Kotla S, Dyukova E, Traylor JG Jr, Orr AW, Chernoff J, Marion TN, Rao GN. Disruption of p21-activated kinase 1 gene diminishes atherosclerosis in apolipoprotein E-deficient mice. Nature Commun. 6: 7450, 2015. PMCID: PMC4480433.
- Singh NK, Hansen DE 3rd, Kundumani-Sridharan V, Rao GN. Both Kdr and Flt1 play a vital role in hypoxia-induced Src-PLD1-PKC-cPLA(2) activation and retinal neovascularization. Blood 121: 1911-1923, 2013. PMCID: PMC3591809.
- Singh NK, Kundumani-Sridharan V, Kumar S, Verma SK, Kotla S, Mukai H, Heckle MR, Rao GN. Protein kinase N1 is a novel substrate of NFATc1-mediated cyclin D1-CDK6 activity and modulates vascular smooth muscle cell division and migration leading to inward blood vessel wall remodeling. J Biol Chem. 287: 36291-36304, 2012. PMCID: PMC3476296.
- Singh NK, Kundumani-Sridharan V, Rao GN. 12/15-Lipoxygenase gene knockout severely impairs ischemia-induced angiogenesis due to lack of Rac1 farnesylation. Blood 118: 5701-5712, 2011. PMCID: PMC3217368.
- Singh NK, Wang D, Kundumani-Sridharan V, Van Quyen D, Niu J, Rao GN. 15-Lipoxygenase-1-enhanced Src-Janus kinase 2-signal transducer and activator of transcription 3 stimulation and monocyte chemoattractant protein-1 expression require redox-sensitive activation of epidermal growth factor receptor in vascular wall remodeling. J Biol Chem. 286: 22478-27488, 2011. PMCID: PMC3121393.
Research Description
Research Support: NIH/NEI (R01EY029709)
Research Projects
Cellular Mechanisms of Pathological retinal Neovascularization: Retinal neovascularization is an ocular manifestation of diabetes, retinopathy of prematurity and age-related macular degeneration, which leads to vision loss. Despite the use of anti-VEGF and laser treatments, progression of retinal neovascularization continues to cause blindness. The development of new therapeutic approaches against retinal neovascularization is limited, because of lack of knowledge about its pathophysiology. Retinal neovascularization is characterized by production of several angiogenic factors, with consequential growth of aberrant new blood vessels on retinal surface that interferes with light transmission and results in vision loss. An elevated level of inflammation and inflammatory mediators have been observed in retinas or vitreous isolated from patients with pathological retinal neovascularization. Therefore, the ability to modulate inflammation and inflammatory mediators and thereby selectively modulating aberrant retinal neovascularization, would be a great strategy in the treatment of pathological retinal neovascularization. The goal of this study is to not only test the role of IL-33 and caspases in hypoxia-induced pathological retinal neovascularization, but also to understand how these inflammatory molecules regulate sprouting angiogenesis and vessel branching.
Regulation of SMC differentiation and migration in restenosis/atherosclerosis: Each year, there are over 7 million cardiovascular bypass and angioplasty procedures performed in the United States. More than one-third of these procedures will have limited durability owing to the formation of intimal hyperplasia, the pathological response of a blood vessel to injury. Although there is no therapy to prevent intimal hyperplasia in bypass grafts, there are some strategies to prevent intimal hyperplasia after angioplasty and stenting. The current antiproliferative agents used to prevent intimal hyperplasia formation inhibit both smooth muscle cell and endothelial cell proliferation. Because these agents prevent the reestablishment of an intact endothelium, patients need to remain on dual antiplatelet therapy indefinitely. An improved strategy to prevent intimal hyperplasia in both surgical bypass and angioplasty and stenting is an unmet clinical need. Pathologically, intimal hyperplasia is a cell-migration–dependent, intimal outgrowth, in which vascular smooth muscle cells (VSMCs) dedifferentiate to a migratory, proliferative, and secretory phenotype. These dedifferentiated VSMCs migrate through the medial layer and invade the intima, where they proliferate and form the hyperplastic neointima. The mechanism by which VSMCs gain motility during intimal hyperplasia development is not fully understood. Our main objective is to target molecules associated with actin and cytoskeleton signaling, that can restrain VSMC translation from contractile to synthetic phase at the initial phase of restenosis.
Research Projects
Cellular Mechanisms of Pathological retinal Neovascularization: Retinal neovascularization is an ocular manifestation of diabetes, retinopathy of prematurity and age-related macular degeneration, which leads to vision loss. Despite the use of anti-VEGF and laser treatments, progression of retinal neovascularization continues to cause blindness. The development of new therapeutic approaches against retinal neovascularization is limited, because of lack of knowledge about its pathophysiology. Retinal neovascularization is characterized by production of several angiogenic factors, with consequential growth of aberrant new blood vessels on retinal surface that interferes with light transmission and results in vision loss. An elevated level of inflammation and inflammatory mediators have been observed in retinas or vitreous isolated from patients with pathological retinal neovascularization. Therefore, the ability to modulate inflammation and inflammatory mediators and thereby selectively modulating aberrant retinal neovascularization, would be a great strategy in the treatment of pathological retinal neovascularization. The goal of this study is to not only test the role of IL-33 and caspases in hypoxia-induced pathological retinal neovascularization, but also to understand how these inflammatory molecules regulate sprouting angiogenesis and vessel branching.
Regulation of SMC differentiation and migration in restenosis/atherosclerosis: Each year, there are over 7 million cardiovascular bypass and angioplasty procedures performed in the United States. More than one-third of these procedures will have limited durability owing to the formation of intimal hyperplasia, the pathological response of a blood vessel to injury. Although there is no therapy to prevent intimal hyperplasia in bypass grafts, there are some strategies to prevent intimal hyperplasia after angioplasty and stenting. The current antiproliferative agents used to prevent intimal hyperplasia formation inhibit both smooth muscle cell and endothelial cell proliferation. Because these agents prevent the reestablishment of an intact endothelium, patients need to remain on dual antiplatelet therapy indefinitely. An improved strategy to prevent intimal hyperplasia in both surgical bypass and angioplasty and stenting is an unmet clinical need. Pathologically, intimal hyperplasia is a cell-migration–dependent, intimal outgrowth, in which vascular smooth muscle cells (VSMCs) dedifferentiate to a migratory, proliferative, and secretory phenotype. These dedifferentiated VSMCs migrate through the medial layer and invade the intima, where they proliferate and form the hyperplastic neointima. The mechanism by which VSMCs gain motility during intimal hyperplasia development is not fully understood. Our main objective is to target molecules associated with actin and cytoskeleton signaling, that can restrain VSMC translation from contractile to synthetic phase at the initial phase of restenosis.