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Bascom Palmer Eye Institute

Dmitry V. Ivanov, Ph.D.

General Information

Dmitry V. Ivanov, Ph.D.

Research Subject

Molecular Mechanisms of Sterile Inflammation, Mechanisms that cells use when determining their fate during retinal development

Vision Science Focus

Retinal Degeneration, Retinal Development, Regenerative Medicine

Published Articles



Research Assistant Professor of Ophthalmology

Current Research

1) Molecular mechanisms that cells use when they choose their fate during retinal development with a view: 1) to grow tissue “in a dish”; 2) to develop regenerative strategies by which retina can heal itself

The retina is generated from multipotent progenitor cells that give rise to ganglion, amacrine, and horizontal cells, as well as to cone photoreceptors in the early stages of retinal development, and to rod photoreceptors, bipolar cells, and Müller glia in the late stages of retinal development. A continuous supply of retinal progenitor cells (RPCs) is required for the steady production of differentiated neurons and complete retinal development. The Notch pathway is an evolutionarily-conserved intercellular signaling cascade that prevents differentiation of RPCs into retinal neurons and facilitates RPC proliferation, thereby maintaining a population of undifferentiated RPCs in the developing retinal tissue. Meanwhile, inhibition of Notch activity facilitates differentiation of RPCs into photoreceptors and ganglion cells, depending on the stage of retinal development. The details of the RPC decision-making mechanism that guides differentiation into these retinal cell types, however, have never been clearly elucidated. To clarify this mechanism, we separated Notch1 receptor-bearing RPCs (Notch1+ RPCs) from retinas at early and late developmental stages and studied the expression profiles of those cells. Our data indicate that Notch1 signaling is a gene network that contains progenitor markers (like Notch1 and Hes5) and pro-neural markers (like Atoh7 and Otx2). Expression of all of these genes should oscillate in RPCs, allowing these cells to maintain an undifferentiated state and proliferate. Nevertheless, RPCs are already predisposed to differentiate into particular retinal cell types when Notch1 inhibitory activity disappears. Our data suggest that at the early stage of retinal development the Notch1 gene network contains at least Notch1, Dll3, Hes5, Atoh7, and Otx2. This network may direct RPCs to differentiate into photoreceptors (cones) and ganglion cells. Meanwhile, the Notch1 gene network at the late stage of retinal development contains at least Notch1, Dll1, Hes5, and Otx2, and therefore may promote RPC differentiation into photoreceptors (rods) and probably bipolar cells. We cannot rule out that, at different stages of retinal development, the Notch1 gene network can contain different pro-neural markers that may direct RPC differentiation into distinct neuronal cell types (for example, Foxn4 lineage). The reconstruction of such gene networks and the crosstalk between them during retinal development could significantly change our views on the mechanisms of retinal neurogenesis.

2) Cell death and inflammation

The common forms of vision loss occur because retinal ganglion cells (RGC) undergo apoptosis and necrosis in retina. However, apoptosis is not as dangerous in the tissue as necrosis. Apoptotic cell death stimulates the production of anti-inflammatory and neuroprotective factors from immune cells that have internalized apoptotic cells. Our studies indicated that therapeutic strategies based on mimicking a systemic increase in levels of apoptotic signals can significantly reduce retinal injury. Meanwhile, endogenous factors (called damage-associated molecular patterns or DAMPs) liberated from necrotic cells mediate cytotoxic pro-inflammatory responses in the tissue. We demonstrated that the released DAMPs cause inflammation and retinal damage. At the same time, suppressing neuronal necrosis in the retina promotes a neuroprotective environment and reduces tissue damage. Thus, necrosis, in contrast to apoptosis, can trigger further RGC death and retinal damage. However, necrosis was often viewed as an accidental and unregulated cellular event. Now we know that that necrosis, like apoptosis, can be regulated and executed by programmed mechanisms (termed 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, this field of research has colossal translational value and will lead to novel therapies. The effectiveness of some of these therapies has already been demonstrated in our published studies.

3) Molecular mechanisms of sterile inflammation in retina

It is known that sterile inflammation, or innate immune response in the absence of live pathogens, is the key player in the pathogenesis of many ocular diseases. But, what are the sources of sterile inflammation? By eliminating such sources or triggers, degenerative conditions can be improved at the source of the problem, rather than simply covering up symptoms with medications. Our lab research brings us closer to providing an answer to this and related questions. We demonstrated that after engaging the DAMPs (Hsp70, Hmgb1, etc.), pattern recognition receptors (PRRs) such as Tlr4 and Rage activate signaling cascades which trigger inflammation and damage in retina. We also identified PRR-dependent signaling cascades, which mediate retinal damage. We found that the Tlr4-dependent Trif signaling cascade contributes directly to retinal damage through loss of RGCs, and indirectly through induction of neurotoxic pro-inflammatory responses. Thus, the results of our studies may yield therapies that allow us to reduce neurotoxic pro-inflammatory responses specifically in retina without globally suppressing the immune system.

4) NFκB signaling in the retina

NFκB signaling plays a key role in regulating inflammatory responses, cell survival, and cell proliferation. It was shown that NFκB signaling is crucial for neuronal survival under neurotoxic conditions. However, our data indicate that RGCs fail to activate NFκB under neurotoxic conditions, though all NFκB family members are present in those same cells. Absence of NFκB activity was associated with an increased level of RGC death. Meanwhile, we demonstrated that glial NFκB promotes retinal damage. Our data suggest that NFκB-regulated pro-inflammatory and redox-active pathways are central to glial neurotoxicity in retina. Thus, our studies have revealed that NFκB activity and NFκB-mediated effects can vary considerably depending on the retinal cell type. In this regard, the therapy aimed at decreasing the glial NFκB activity and increasing activity of the NFκB signaling cascade directly in RGCs may represent a promising neuroprotective strategy for neurodegenerative disorders of the retina.