Retinal detachment (RD) and subsequent neurodegeneration of the retina continues to be a leading cause of visual impairment. In patients with sustained RD, progressive visual decline due to photoreceptor cell death is common and leads to a significant decrease in visual acuity. Numerous pathological changes occur in the detached retina and studies in human patient samples and in animal models have shown rapid photoreceptor cell death in response to RD. However, the underlying processes that facilitate this death have remained elusive and currently no treatments exist, aside from surgery to reattach the retina. Early inflammatory mediators are up-regulated in the eyes of patients with RD; of particular interest are those of the complement system. The complement system is an intricate immune surveillance system that is able to discriminate between healthy and diseased host tissue, and modulates the elimination and repair of host tissue accordingly. Within the ocular microenvironment, the alternative complement cascade exhibits low levels of constitutive activation and is tightly controlled by intraocular complement regulatory proteins. We have recently found that the alternative complement pathway is a vital regulator of photoreceptor cell death in response to injury. However, little is known about how this pathway becomes activated in RD. Interestingly, the complement receptors are potent downstream mediators of inflammation leading to the recruitment of immune cells and up- regulation of both complement proteins as well as pro-inflammatory cytokines from the local microenvironment Our preliminary data strongly implicates the complement receptors in photoreceptor cell death. To this end we hypothesize that the complement receptors, and their respective ligands, help facilitate a response against the stressed photoreceptors in the damaged retina, specifically targeting these cells for removal and increasing the inflammatory potential in the retinal microenvironment exacerbating this degenerative disease. We will utilize a well-defined mouse model of RD, in which a subretinal injection of sodium hyaluronate is used to create a detachment. The mouse RD model will allow us to take advantage of well-established genetic manipulation platforms in mice in a controlled setting. In order to characterize the role of the innate immune system in photoreceptor cell death we will: 1) Determine the role of complement receptors in mediating photoreceptor cell death in RD (Aim I); 2) Identify the regulatory mechanisms of complement production in response to RD (Aim II) and 3) To define the role of the complement receptors and microglia in RD disease pathogenesis (Aim III). It is our hope that this proposal will allow us to further characterize the role of the complement system in photoreceptor loss during RD, leading to therapies that protect individuals with RD as an adjuvant therapeutic agent to retinal detachment surgery.

Public Health Relevance

In retinal detachment (RD), photoreceptor degeneration is a primary outcome leading to significant visual impairment. Recent evidence has implicated the alternative complement system as a viable therapeutic target in ocular degenerations. Our proposal will determine the molecular and cellular sequelae that regulate and/or participate in alternative complement pathway mediated neuroinflammation during RD disease progression.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY027303-02
Application #
9685221
Study Section
Diseases and Pathophysiology of the Visual System Study Section (DPVS)
Program Officer
Mckie, George Ann
Project Start
2018-05-01
Project End
2021-04-30
Budget Start
2019-05-01
Budget End
2020-04-30
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Massachusetts Eye and Ear Infirmary
Department
Type
DUNS #
073825945
City
Boston
State
MA
Country
United States
Zip Code
02114
Inafuku, Saori; Klokman, Garrett; Connor, Kip M (2018) The Alternative Complement System Mediates Cell Death in Retinal Ischemia Reperfusion Injury. Front Mol Neurosci 11:278
Okunuki, Yoko; Mukai, Ryo; Pearsall, Elizabeth A et al. (2018) Microglia inhibit photoreceptor cell death and regulate immune cell infiltration in response to retinal detachment. Proc Natl Acad Sci U S A 115:E6264-E6273