LIF expression is induced in M?ller cells in response to photoreceptor stress caused by inherited mutations. Inhibiting the LIF receptor with antagonists, or knocking out the co-receptor gp130, or the signaling target STAT3 in photoreceptors, accelerates degeneration. These results show that induced LIF delays the onset and rate of retinal degeneration. We have also shown that expression of LIF decreases significantly during the time of rapid photoreceptor degeneration, and our published studies show that we can dramatically delay inherited degeneration by keeping LIF levels elevated. These results show that progression of disease is regulated by expression of LIF in M?ller cells. Understanding both the induction of LIF early in disease and its suppressed expression later in disease is necessary to understand one mechanism that can determine the age of onset and rate of retinal degeneration. Understanding the regulation of LIF would also lead to the identification of potential targets that can be manipulated to promote neuronal survival by inducing and maintaining LIF expression. The goal of this project is to determine both the mechanism for induced LIF expression and the mechanism for reduction of expression that coincides with rapid degeneration. The proposal will determine the role of three receptor-signaling pathways that can coordinate to either induce or maintain LIF expression, and will determine the role to the LIF cis-acting elements in suppressing LIF expression

Public Health Relevance

This project is focused on identifying the mechanism by which the neural retina induces endogenous neuroprotection. This system is induced in M ller cells as a mechanism to delay retinal degeneration. The significance of this proposed study is that we will identify mechanisms for controlling both the induction of the neuroprotective factor leukemia inhibitory factor (LIF) early in disease and its suppressed expression during the rapid phase of retinal degeneration. This is important for two reasons. First; understanding the regulation of LIFexpression will identify factors that determine the age of onset and the rate of degeneration in patients with retinal degeneration. Second; understanding the regulation of LIF would also lead to the identification of potential targets that can be manipulated to promote neuronal survival by inducing and maintaining LIF expression.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY016459-09
Application #
8630345
Study Section
Special Emphasis Panel (BVS)
Program Officer
Neuhold, Lisa
Project Start
2005-04-01
Project End
2018-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
9
Fiscal Year
2014
Total Cost
$361,488
Indirect Cost
$111,488
Name
University of Florida
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Xu, Lei; Ash, John D (2016) The Role of AMPK Pathway in Neuroprotection. Adv Exp Med Biol 854:425-30
Reagan, Alaina; Gu, Xiaowu; Hauck, Stefanie M et al. (2016) Retinal Caveolin-1 Modulates Neuroprotective Signaling. Adv Exp Med Biol 854:411-8
Abrahan, Carolina; Ash, John D (2016) Erratum to: The Potential Use of PGC-1α and PGC-1β to Protect the Retina by Stimulating Mitochondrial Repair. Adv Exp Med Biol 854:E1
Ildefonso, Cristhian J; Jaime, Henrique; Brown, Emily E et al. (2016) Targeting the Nrf2 Signaling Pathway in the Retina With a Gene-Delivered Secretable and Cell-Penetrating Peptide. Invest Ophthalmol Vis Sci 57:372-86
Abrahan, Carolina; Ash, John D (2016) The Potential Use of PGC-1α and PGC-1β to Protect the Retina by Stimulating Mitochondrial Repair. Adv Exp Med Biol 854:403-9
Fu, Suhua; Zhu, Meili; Ash, John D et al. (2014) Investigating the role of retinal Müller cells with approaches in genetics and cell biology. Adv Exp Med Biol 801:401-5
Hazra, S; Jarajapu, Y P R; Stepps, V et al. (2013) Long-term type 1 diabetes influences haematopoietic stem cells by reducing vascular repair potential and increasing inflammatory monocyte generation in a murine model. Diabetologia 56:644-53
Chollangi, Srinivas; Mather, Timothy; Rodgers, Karla K et al. (2012) A unique loop structure in oncostatin M determines binding affinity toward oncostatin M receptor and leukemia inhibitory factor receptor. J Biol Chem 287:32848-59
Chucair-Elliott, Ana J; Elliott, Michael H; Wang, Jiangang et al. (2012) Leukemia inhibitory factor coordinates the down-regulation of the visual cycle in the retina and retinal-pigmented epithelium. J Biol Chem 287:24092-102
Li, Xiaoman; McClellan, Mark E; Tanito, Masaki et al. (2012) Loss of caveolin-1 impairs retinal function due to disturbance of subretinal microenvironment. J Biol Chem 287:16424-34

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