Dmitry V. Ivanov, Ph.D.

Current Research

1. The role of the DNA demethylation pathway in retinal development: Understanding the mechanisms of retinal development is of vital importance in the proposal of therapeutic approaches to restoring visual function via the regeneration of lost retinal neurons. Though much progress has been made in the understanding of signaling cascades driving retinal development, the role of epigenetic mechanisms remains to be explored as meticulously. In order to fill this gap, we evaluated the contribution of the DNA methylation and DNA demethylation pathways to retinal development in recent studies. To this end, we studied DNA methylation in genomes of retinal progenitor cells (RPCs) and retinal neurons using a combination of whole genome bisulfite sequencing (WGBS) data and bioinformatic approaches (Figure 1). Our data suggest that the DNA demethylation pathway—not the DNA methylation pathway—is crucial for retinal development.

1. Dvoriantchikova, G., Seemungal, R.J., & Ivanov, D. (2019) The epigenetic basis for the impaired ability of adult murine retinal pigment epithelium cells to regenerate retinal tissue. Sci Rep. Mar 7;9(1):3860. doi: 10.1038/s41598-019-40262-w. PubMed PMID: 30846751; PubMed Central PMCID: PMC6405859.
2. Dvoriantchikova, G., Seemungal, R.J., & Ivanov, D. (2019). Development and epigenetic plasticity of murine Müller glia. Biochim Biophys Acta Mol Cell Res. Oct;1866(10):1584-1594. doi: 10.1016/j.bbamcr.2019.06.019. Epub 2019 Jul 2. PubMed PMID: 31276697.
3. Dvoriantchikova, G., Seemungal, R.J., & Ivanov, D. (2019). DNA Methylation Dynamics During the Differentiation of Retinal Progenitor Cells Into Retinal Neurons Reveal a Role for the DNA Demethylation Pathway. Front. Mol. Neurosci. 12:182. doi: 10.3389/fnmol.2019.00182

2. Notch signaling in ocular development: The Dll1/Jag1/Notch pathway is a highly sophisticated signaling cascade, controlling cell-fate and tissue patterning with major cellular processes depending on the levels of Notch ligands, Dll1, and Jag1 (Figure 2). Dll1/Notch signaling, via a lateral inhibition mechanism, promotes a “salt-and-pepper” pattern when neighboring cells adopt two different fates (sender “S” and receiver “R”). Jag1/Notch, via lateral induction, drives neighboring cells to adopt the same fate—a hybrid “S/R” phenotype. The Jag1/Notch phenotype involves a double positive feedback loop, giving it an advantage over the Dll1/Notch phenotype: the Jag1/Notch phenotype promotes itself. Meanwhile, fringe proteins (Lfng and Mfng) switch Notch signaling from lateral induction to lateral inhibition, thereby promoting Dll1/Notch signaling over Jag1/Notch. Our data and literature suggest that retinal progenitor cells (RPCs) at the early stage of retinal development, and developing Müller glia at the late stage of retinal development, adopt the “R” Dll1/Notch-regulated fate, while RPCs differentiating into retinal neurons adopt the “S” phenotype. At the same time, our data and literature suggest that lacrimal gland epithelial cells have the typical Jag1/Notch hybrid “S/R” phenotype and easily undergo an epithelial-to-mesenchymal transition (EMT). We also found that Notch signaling regulates branching morphogenesis in the developing lacrimal gland. Our data and literature suggest that RPE cells also have the typical Jag1/Notch hybrid “S/R” phenotype. Thus, Notch signaling plays critical roles in many aspects of ocular organogenesis and by learning how to satisfactorily manipulate Notch signaling, we may significantly improve latent regenerative abilities inherent in ocular tissues.

1. Dvoriantchikova, G., Perea-Martinez, I., Pappas, S., Barry, A.F., Danek, D., Dvoriantchikova, X., Pelaez, D., & Ivanov, D. (2015). Molecular Characterization of Notch1 Positive Progenitor Cells in the Developing Retina. PLoS One.10(6), e0131054. PMCID: PMC4474692.
2. Dvoriantchikova, G., Tao, W., Pappas, S., Gaidosh, G., Tse, D.T., Ivanov, D*., & Pelaez, D*. (2017). Molecular Profiling of the Developing Lacrimal Gland Reveals Putative Role of Notch Signaling in Branching Morphogenesis. Invest Ophthalmol Vis Sci. 58(2), 1098-1109. PMCID: PMC5308770. * - DI and DP are joint senior authors
3. Dvoriantchikova, G., Seemungal, R.J., & Ivanov, D. (2019). Development and epigenetic plasticity of murine Müller glia. Biochim Biophys Acta Mol Cell Res. Oct;1866(10):1584-1594. doi: 10.1016/j.bbamcr.2019.06.019. Epub 2019 Jul 2. PubMed PMID: 31276697.
4. Ivanov, D. (2019), Notch signaling-induced oscillatory gene expression may drive neurogenesis in the developing retina. Front. Mol. Neurosci. Sep 19;12:226. doi: 10.3389/fnmol.2019.00226. eCollection 2019. PMID: 31607861 PMCID: PMC6761228

3. Cell death and inflammation: Common forms of vision loss occur when retinal ganglion cells (RGCs) undergo apoptosis and/or necrosis in the retina. Apoptosis, however, is not as dangerous to the surrounding tissue as necrosis. Apoptotic cell death stimulates the production of anti-inflammatory and neuroprotective factors from immune cells that have internalized the apoptotic cells. Our studies indicate that therapeutic strategies based on mimicking a systemic increase in levels of apoptotic signals can significantly reduce retinal injury. In contrast, endogenous factors called damage-associated molecular patterns (DAMPs) liberated from necrotic cells mediate cytotoxic, pro-inflammatory responses in retinal tissue. We demonstrated that these DAMPs, released from lysed necrotic cells, lead to inflammation and retinal damage. We also found that suppressing neuronal necrosis in the retina promotes a neuroprotective environment and reduces tissue damage. Thus, in contrast to apoptosis, necrosis can trigger further RGC death and retinal damage. Historically viewed as an entirely accidental and unregulated cellular event, we now know that that necrosis, like apoptosis, can be regulated and executed by programmed mechanisms (“necroptosis”). We demonstrated that necroptosis contributes to retinal injury through direct loss of RGCs and induction of associated inflammatory responses. Since necroptosis can be regulated, research into its exact mechanisms harbors colossal translational value that could lead to novel therapies. The effectiveness of some of these therapies has already been demonstrated in our published studies.

1. Dvoriantchikova, G., Agudelo, C., Hernandez, E., Shestopalov, V.I., & Ivanov, D. (2009). Phosphatidylserine-containing liposomes promote maximal survival of retinal neurons after ischemic injury. J Cereb Blood Flow Metab., 29(11), 1755-1759. 
2. Dvoriantchikova, G., Degterev, A., & Ivanov, D. (2014). Retinal ganglion cell (RGC) programmed necrosis contributes to ischemia-reperfusion-induced retinal damage. Exp Eye Res. 123:1-7. PMCID: PMC4059599.
3. Santos, A.R., Dvoriantchikova, G., Li, Y., Mohammad, G., Abu El-Asrar, A.M., Wen, R., & Ivanov, D. (2014). Cellular mechanisms of high mobility group 1 (HMGB-1) protein action in the diabetic retinopathy. PLoS One., 9(1), e87574. PMCID: PMC3909191
4. Madsen, P.M., Pinto, M., Patel, S., McCarthy, S., Gao, H., Taherian, M., Karmally, S., Pereira, C.V., Dvoriantchikova, G., Ivanov, D., Tanaka, K.F., Moraes, C.T., & Brambilla, R. (2017). Mitochondrial DNA Double-Strand Breaks in Oligodendrocytes Cause Demyelination, Axonal Injury, and CNS Inflammation. J Neurosci. 37(42), 10185-10199. PMCID: PMC5647772.

4. Molecular mechanisms of sterile inflammation in the retina: It is known that sterile inflammation, or the innate immune response in the absence of live pathogens, is a key player in the pathogenesis of many ocular diseases. But what are the sources of sterile inflammation? Identifying and eliminating such sources/triggers could ease degenerative conditions by addressing their root causes—rather than simply covering up symptoms. My lab’s research brings us closer to providing an answer to this and related questions. We demonstrated that after engaging DAMPs (Hsp70, Hmgb1, etc.), pattern recognition receptors (PRRs), such as Tlr4 and Rage, activate signaling cascades that trigger inflammation and retinal damage. We also identified new PRR-dependent signaling cascades that mediate retinal damage. We found that the Tlr4/Trif-dependent signaling cascade contributes to retinal damage both directly (through loss of RGCs) and indirectly (through induction of neurotoxic pro-inflammatory responses). The results of our work provide an intellectual foundation for the development of new therapeutic strategies that could reduce neurotoxic, pro-inflammatory responses specifically in the retina without globally suppressing the immune system (Figure 3).

1. Dvoriantchikova, G., Hernandez, E., Grant, J., Santos, A.R., Yang, H., & Ivanov, D. (2011). The high-mobility group box-1 nuclear factor mediates retinal injury after ischemia reperfusion. Invest Ophthalmol Vis Sci., 52(10), 7187-7194. PMCID: PMC3207720
2. Dvoriantchikova, G., Santos, A.R., Saeed, A.M., Dvoriantchikova, X., & Ivanov, D. (2014). Putative role of protein kinase C in neurotoxic inflammation mediated by extracellular heat shock protein 70 after ischemia-reperfusion. J Neuroinflammation., 11, 81. PMCID: PMC4001362
3. Dvoriantchikova, G., Santos, A.R., Danek, D., Dvoriantchikova, X., & Ivanov, D. (2014). The TIR-domain-containing adapter inducing interferon-β-dependent signaling cascade plays a crucial role in ischemia-reperfusion-induced retinal injury, whereas the contribution of the myeloid differentiation primary response 88-dependent signaling cascade is not as pivotal. Eur J Neurosci., 40(3), 2502-2512. PMCID: PMC4122625
4. Tse, B.C., Dvoriantchikova, G., Tao, W., Gallo, R.A., Lee, J.Y., Pappas, S., Brambilla, R., Ivanov, D., Tse, D.T. & Pelaez, D. (2018). Tumor Necrosis Factor Inhibition in the Acute Management of Traumatic Optic Neuropathy. Invest Ophthalmol Vis Sci. 59(7), 2905-2912. PMCID: PMC5989875.

Figure 3. The “damage chain reaction”