The macrophage is a key component of the innate arm of immunity and is critical in regulating initial immune response to tumors, infections and in inflammation. The macrophage is also a central player in sustaining immune privilege in the eye. Immunosenescence is characterized by age-related changes in both the innate and adaptive compartments of the immune system. Innate immunity, specifically macrophage function, has received particular attention in the eye as it can modulate developmental and post-developmental angiogenesis. Ocular neovascularization plays a central role in visual impairment and blindness in several disease states of the eye, including age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, and intraocular tumors. The work described in this proposal will help elucidate the mechanisms by which senescence induces a functional drift in macrophages towards a deleterious pro-angiogenic phenotype. Our studies will also test how altering macrophage polarization determines angiogenic fate in the eye. These questions are especially relevant to the importance of macrophages in AMD. These goals will be accomplished by: a) Quantifying age-related changes in IL-10 activated signaling pathways in macrophages that lead to loss of anti-angiogenic function and b) Demonstrating that abnormal processing of cholesterol, a dominant component of drusen, causes old macrophages to become pro- angiogenic. Public Health Relevance: Angioproliferative eye diseases account for a significant majority of blindness burden across all age groups. Mechanisms that lead to immune dysfunction as identified in this proposal that are relevant to the pathophysiology of abnormal angiogenesis will help us devise immune based therapies that ameliorate disease progression and ultimately blindness.

Public Health Relevance

Immune cells and cytokines secreted by immune cells, specifically macrophages, are emerging as central players in regulating eye diseases associated with abnormal blood vessel growth. These include age-related macular degeneration, retinopathy of prematurity, and diabetic retinopathy.
We aim to understand the mechanisms by which macrophage dysfunction promotes disease progression and hope to provide new insights in order to design future therapies to prevent blindness from these diseases.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY019287-04
Application #
8527781
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Mckie, George Ann
Project Start
2010-09-30
Project End
2015-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
4
Fiscal Year
2013
Total Cost
$311,904
Indirect Cost
$106,704
Name
Washington University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Apte, Rajendra S (2016) Targeting Tissue Lipids in Age-related Macular Degeneration. EBioMedicine 5:26-7
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Zhou, Z; Doggett, T A; Sene, A et al. (2015) Autophagy supports survival and phototransduction protein levels in rod photoreceptors. Cell Death Differ 22:488-98
Sene, Abdoulaye; Chin-Yee, David; Apte, Rajendra S (2015) Seeing through VEGF: innate and adaptive immunity in pathological angiogenesis in the eye. Trends Mol Med 21:43-51
Nakamura, Rei; Sene, Abdoulaye; Santeford, Andrea et al. (2015) IL10-driven STAT3 signalling in senescent macrophages promotes pathological eye angiogenesis. Nat Commun 6:7847
Oladipupo, Sunday S; Smith, Craig; Santeford, Andrea et al. (2014) Endothelial cell FGF signaling is required for injury response but not for vascular homeostasis. Proc Natl Acad Sci U S A 111:13379-84
Sene, Abdoulaye; Apte, Rajendra S (2014) Eyeballing cholesterol efflux and macrophage function in disease pathogenesis. Trends Endocrinol Metab 25:107-14
Silberman, Dafne M; Ross, Kenneth; Sande, Pablo H et al. (2014) SIRT6 is required for normal retinal function. PLoS One 9:e98831

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