In the previous funding period, we demonstrated that diabetic individuals and mice demonstrate dysfunctional endothelial progenitor cells. These bone marrow (BM) derived cells are released into the circulation in an abnormal manner due to diabetes-induced BM neuropathy. This BM neuropathy leads to dysregulation in the circadian release of these cells into the circulation. These BM changes precede development of diabetic retinopathy (DR) linking BM neuropathy for the first time to DR. Diabetic BM supernatants, but not control, contain high levels of monocyte/macrophage-colony stimulating factor (M-CSF) and diabetic mice exhibit an increase number of monocytes in the retina and circulation. Based on these findings, we hypothesize that: Diabetic BM denervation initiates HSC/progenitor dysfunction that leads to an increase in total monocytes generated, this, coupled with increased expression of CCL2 (monocyte chemoattractent protein-1) by retinal glia results in excessive levels of the pro-inflammatory (M1) monocytes in the diabetic retina. In addition, diminished levels of CX3CL1 (fractalkine) expression by dysfunctional neurons heightens the inflammatory response of resident microglia. This imbalance leads to a neural inflammation that accelerates DR pathogenesis. We will test this hypothesis both in vitro and in vivo through the simultaneous exploration of the following aims:
Aim 1 : To determine whether diabetes induced BM neuropathy is responsible for increased M-CSF production by BM stromal cells which shifts hematopoiesis towards generation of excessive numbers of monocytes, in particular pro-inflammatory Gr1+/CCR2+/CX3CR1lo monocytes, rather than the protective Gr1-/CCR2-/CX3CR1hi monocytes.
Aim 2 : To determine the roles of CCL2 and CX3CL1 in DR inflammation and to test whether restoration of the balance of CCR2+CX3CR1lo and CCR2-/CX3CR1hi monocytes and simultaneous restoration of levels of endothelial progenitors to retinal vasculature will prevent o reverse DR in T1D mice.
Aim 3 : Our hypothesis predicts that circulating pro- inflammatory Gr1+/CCR2+i/CX3CR1lo cells will cause endothelial cell activation, promote leukostasis and result in enhanced retinal permeability whereas Gr1-/CCR2-/CX3CR1hi cells will protect the BRB in diabetes. We will examine the effects of manipulating these subsets on the progression of DR. Targeting monocyte subtypes may represent an ideal strategy for DR prevention and treatment. CellMax?

Public Health Relevance

This proposal examines how loss of innervation (neuronal support) to the bone marrow in diabetes impacts the behavior of bone marrow derived cells, specifically the vascular reparative cells and the monocytes. We will examine why the diabetic bone marrow produces too few reparative cells and too many inflammatory cells that then enter the circulation, migrate into the retina and lead to histological and functional abnormalities associated with diabetic retinopathy.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY007739-24
Application #
8735950
Study Section
Special Emphasis Panel (DPVS)
Program Officer
Shen, Grace L
Project Start
2013-09-07
Project End
2016-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
24
Fiscal Year
2014
Total Cost
$452,378
Indirect Cost
$41,448
Name
Indiana University-Purdue University at Indianapolis
Department
Ophthalmology
Type
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Shaw, Lynn Calvin; Li Calzi, Sergio; Li, Nan et al. (2018) Enteral Arg-Gln Dipeptide Administration Increases Retinal Docosahexaenoic Acid and Neuroprotectin D1 in a Murine Model of Retinopathy of Prematurity. Invest Ophthalmol Vis Sci 59:858-869
Song, Chunjuan; Mitter, Sayak K; Qi, Xiaoping et al. (2017) Oxidative stress-mediated NF?B phosphorylation upregulates p62/SQSTM1 and promotes retinal pigmented epithelial cell survival through increased autophagy. PLoS One 12:e0171940
Abcouwer, Steven F (2017) Müller Cell-Microglia Cross Talk Drives Neuroinflammation in Diabetic Retinopathy. Diabetes 66:261-263
Li, Wennan; Chen, Xingjuan; Riley, Ashley M et al. (2017) Long-term spironolactone treatment reduces coronary TRPC expression, vasoconstriction, and atherosclerosis in metabolic syndrome pigs. Basic Res Cardiol 112:54
Coughlin, Brandon A; Feenstra, Derrick J; Mohr, Susanne (2017) Müller cells and diabetic retinopathy. Vision Res 139:93-100
Yan, Yuanqing; Gao, Ruli; Trinh, Thao L P et al. (2017) Immunodeficiency in Pancreatic Adenocarcinoma with Diabetes Revealed by Comparative Genomics. Clin Cancer Res 23:6363-6373
Bhatwadekar, Ashay D; Beli, Eleni; Diao, Yanpeng et al. (2017) Conditional Deletion of Bmal1 Accentuates Microvascular and Macrovascular Injury. Am J Pathol 187:1426-1435
Caballero, Sergio; Kent, David L; Sengupta, Nilanjana et al. (2017) Bone Marrow-Derived Cell Recruitment to the Neurosensory Retina and Retinal Pigment Epithelial Cell Layer Following Subthreshold Retinal Phototherapy. Invest Ophthalmol Vis Sci 58:5164-5176
Bhatwadekar, Ashay D; Duan, Yaqian; Korah, Maria et al. (2017) Hematopoietic stem/progenitor involvement in retinal microvascular repair during diabetes: Implications for bone marrow rejuvenation. Vision Res 139:211-220
Basavarajappa, Halesha D; Sulaiman, Rania S; Qi, Xiaoping et al. (2017) Ferrochelatase is a therapeutic target for ocular neovascularization. EMBO Mol Med 9:786-801

Showing the most recent 10 out of 93 publications