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
Jarajapu, Yagna P R; Hazra, Sugata; Segal, Mark et al. (2014) Vasoreparative dysfunction of CD34+ cells in diabetic individuals involves hypoxic desensitization and impaired autocrine/paracrine mechanisms. PLoS One 9:e93965
Wang, Qi; Tikhonenko, Maria; Bozack, Svetlana N et al. (2014) Changes in the daily rhythm of lipid metabolism in the diabetic retina. PLoS One 9:e95028
Wang, Qi; Bozack, Svetlana N; Yan, Yuanqing et al. (2014) Regulation of retinal inflammation by rhythmic expression of MiR-146a in diabetic retina. Invest Ophthalmol Vis Sci 55:3986-94
Keats, Emily C; Dominguez 2nd, James M; Grant, Maria B et al. (2014) Switch from canonical to noncanonical Wnt signaling mediates high glucose-induced adipogenesis. Stem Cells 32:1649-60
Hu, Ping; Thinschmidt, Jeffrey S; Yan, Yuanqing et al. (2013) CNS inflammation and bone marrow neuropathy in type 1 diabetes. Am J Pathol 183:1608-20
Nguyen, Dung V; Li Calzi, Sergio; Shaw, Lynn C et al. (2013) An ocular view of the IGF-IGFBP system. Growth Horm IGF Res 23:45-52
Abcouwer, Steven F (2013) Angiogenic Factors and Cytokines in Diabetic Retinopathy. J Clin Cell Immunol Suppl 1:
Abcouwer, Steven F (2013) Direct effects of PPAR* agonists on retinal inflammation and angiogenesis may explain how fenofibrate lowers risk of severe proliferative diabetic retinopathy. Diabetes 62:36-8
Abcouwer, Steven F; Lin, Cheng-Mao; Shanmugam, Sumathi et al. (2013) Minocycline prevents retinal inflammation and vascular permeability following ischemia-reperfusion injury. J Neuroinflammation 10:149
Nakagawa, Takahiko; Tanabe, Katsuyuki; Croker, Byron P et al. (2011) Endothelial dysfunction as a potential contributor in diabetic nephropathy. Nat Rev Nephrol 7:36-44

Showing the most recent 10 out of 20 publications