Studies from our laboratory over the past decade have found the existence of a novel light-dependent insulin receptor (IR) signaling pathway in rod photoreceptors. We have discovered that IR activation is functionally important for rod survival, since its deletion in rods resulted in the loss of neuroprotective survival signaling. This novel pathway uses growth factor receptor bound protein (Grb14), an upstream regulator of IR, and requires photobleaching of rhodopsin for membrane targeting. Grb14 protects light-dependent IR activation in rod photoreceptors against dephosphorylation by PTP1B. Light-activated IR is subsequently associated with phosphoinositide 3-kinase (PI3K), a cell survival factor, and thus regulates the downstream survival pathway. These studies suggest that rhodopsin photoexcitation may trigger signaling events alternative to the classical transducin activation. Recently, it was suggested that the IR signaling pathway is important for cone photoreceptor survival in retinitis pigmentosa (RP) models since systemic administration of insulin delays the death of cone photoreceptors. We found that insulin-like growth factor-1 receptor (IGF-1R) also activates PI3K and Akt survival pathway in rods under light stress. It is our hypothesis that IR/IGF-1R signaling pathways are important for survival and maintenance of rod and cone photoreceptor structure and function. The long-term goal of our project is to gain a greater understanding of the intracellular signaling pathways that provide neuroprotection to both rod and cone photoreceptor cells. The specific objective is to investigate the role of IR and IGF-1R in the regulation of photoreceptor structure and function. To this end, we will determine the mechanism by which Grb14 activates the IR and determine the functional roles of IR and IGF-1R in both rod and cone photoreceptor cells. We will utilize a combination of genetic, molecular, and biochemical approaches to address our specific aims. Results from these studies will lead to a better understanding the roles of IR and IGF-1R signaling in photoreceptor structure, function and survival.

Public Health Relevance

Insulin receptors (IR) and insulin signaling proteins are widely distributed throughout the central nervous system (CNS). Disregulation of IR signaling in the CNS has been linked to the pathogenesis of neurodegenerative disorders such as Alzheimer's and Parkinson's disease. In retinal rods, IR signaling is neuroprotective, and recently it was shown that insulin delays the death of cone photoreceptor in retinitis pigmentosa animal models. Besides IR, insulin-like growth factor-1 receptors (IGF-1R) are also expressed in both rods and cones;however, their functional role has not been elucidated. Our studies suggest that protein tyrosine phosphatase 1B (PTP1B) negatively regulated neuroprotective survival signaling of the IR. Our studies also suggest that a defect in the photobleaching of rhodopsin and mutations in rhodopsin gene enhances the activity of PTP1B and this activated activity could down regulate the IR survival signaling. Controlling the PTP1B activity and activating the IR signaling would provide sustained neuroprotection to both rods and cones. Our new and innovative approaches to target PTP1B will facilitate future translational application of our work, with the goal of applying our findings to the clinical care of human retinal degenerations. Studies proposed in this grant application would help to understand the functional roles of IR and IGF-1R in photoreceptor structure, function and survival.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY016507-08
Application #
8526462
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Neuhold, Lisa
Project Start
2005-04-01
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
8
Fiscal Year
2013
Total Cost
$337,440
Indirect Cost
$109,440
Name
University of Oklahoma Health Sciences Center
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
878648294
City
Oklahoma City
State
OK
Country
United States
Zip Code
73117
Rajala, Raju V S; Rajala, Ammaji; Morris, Andrew J et al. (2014) Phosphoinositides: minor lipids make a major impact on photoreceptor cell functions. Sci Rep 4:5463
Woodruff, Michael L; Rajala, Ammaji; Fain, Gordon L et al. (2014) Modulation of mouse rod photoreceptor responses by Grb14 protein. J Biol Chem 289:358-64
Rajala, Ammaji; Wang, Yuhong; Zhu, Ye et al. (2014) Nanoparticle-assisted targeted delivery of eye-specific genes to eyes significantly improves the vision of blind mice in vivo. Nano Lett 14:5257-63
Rajala, Ammaji; Gupta, Vivek K; Anderson, Robert E et al. (2013) Light activation of the insulin receptor regulates mitochondrial hexokinase. A possible mechanism of retinal neuroprotection. Mitochondrion 13:566-76
Rajala, Ammaji; Dighe, Radhika; Agbaga, Martin-Paul et al. (2013) Insulin receptor signaling in cones. J Biol Chem 288:19503-15
Rajala, Ammaji; Dilly, Ashok K; Rajala, Raju Vs (2013) Protein tyrosine phosphatase-1B regulates the tyrosine phosphorylation of the adapter Grb2-associated binder 1 (Gab1) in the retina. Cell Commun Signal 11:20
Rajala, Raju V S; Basavarajappa, Devaraj K; Dighe, Radhika et al. (2013) Spatial and temporal aspects and the interplay of Grb14 and protein tyrosine phosphatase-1B on the insulin receptor phosphorylation. Cell Commun Signal 11:96
Gupta, Vivek K; Rajala, Ammaji; Rajala, Raju V S (2012) Ras-associating domain proteins: a new class of cyclic nucleotide-gated channel modulators. Adv Exp Med Biol 723:777-82
Basavarajappa, Devaraj K; Gupta, Vivek K; Rajala, Raju V S (2012) Protein tyrosine phosphatase 1B: a novel molecular target for retinal degenerative diseases. Adv Exp Med Biol 723:829-34
Rajala, Raju V S; Rajala, Ammaji; Gupta, Vivek K (2012) Conservation and divergence of Grb7 family of Ras-binding domains. Protein Cell 3:60-70

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