Microglia are resident myeloid-lineage cells in both the CNS and in the eye and function in the maintenance of normal tissue. Retinal microglia can become activated and/or dysregulated during disease, and thus affect disease progression in retinitis pigmentosa. Understanding the biology of microglia is a challenge due to absence of markers and molecular microglia signatures. Recently, we identified a homeostatic molecular microglia signature which provides new tools for investigating retinal microglial biology and the possibility of targeting retinal microglia for the treatment of retinitis pigmentosa. Using our new microglial markers, we investigated microglia in the rd1 murine models of RP. We found increased numbers of resident microglia but no infiltration of monocytes in the retinal. Most importantly, we found that intravitreal transfer of microglia from animals with RP into normal animals, resulted in photoreceptor loss. Consistent with this, intravitreal transfer of retinal microglia from normal animals into animals with RP reduced photoreceptors loss. We hypothesize that in RP, microglia proliferate and acquire a cytotoxic phenotype mediated by intrinsic activation of the TREM2-APOE pathway which suppresses microglia homeostatic molecular properties and leads to uncontrolled chronic inflammation and photoreceptors damage. Treatments aimed to target microglia by suppressing the TREM2-APOE pathway is associated with activation of both the TGF? pathway and MERTK which abrogates the inflammatory microglial phenotype and restores retinal microglial homeostatic properties. This provides a new direction for studying RP and development of novel therapies that target microglia. We believe that an innovative feature of our approach is that it is a mutation- independent approach that applies to RP independent of the genetic mutation. In addition, there is a translational aspect to the proposed work as we will investigate human eyes with our recently described microglial antibodies. We will address the following specific aims:
Aim 1. Identify molecular pathways affected in retinal microglia in mouse models and human RP.
Aim 2. Target the TREM2-APOE-SPP1 pathway to inhibit MGnD-cytotoxic microglia in rd mice.
Aim 3. Restore M0-homeostatic microglia via TGF?1-MERTK signaling in rd mice.

Public Health Relevance

The focus of this grant proposal is to characterize retinal microglia and how they regulate and/or participate in retinal damage in both animal models of retinitis pigmentosa and in eyes from human subjects. We will investigate whether retinitis pigmentosa in animal models can be treated by specifically targeting and modulating microglia. We will use new technology and approaches to understand features of microglia cells that can then be exploited to develop novel microglia-targeting therapies to treat humans with retinitis pigmentosa.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY027921-01
Application #
9301253
Study Section
Diseases and Pathophysiology of the Visual System Study Section (DPVS)
Program Officer
Mckie, George Ann
Project Start
2017-09-30
Project End
2020-06-30
Budget Start
2017-09-30
Budget End
2018-06-30
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115