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High-probability grants
According to our matching algorithm, Yingbin Fu is the likely recipient of the following grants.
Years |
Recipients |
Code |
Title / Keywords |
Matching score |
2012 — 2014 |
Fu, Yingbin |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Cone Opsins in Photoreceptor Degeneration
DESCRIPTION (provided by applicant): Retinoid isomerase, RPE65, and Lecithin-retinol acyltransferase (LRAT) are important in recycling 11-cis- retinal in retinal pigment epithelium (RPE). Mutations in either gene lead to Leber congenital amaurosis (LCA), an inherited retinal degenerative disease characterized by severe loss of vision in childhood and early degeneration of cones followed by rods. The main pathologic features are recapitulated by two models, Rpe65-/- and Lrat-/- in which 11-cis-retinal is lacking. However, the mechanisms responsible for early cone degeneration in both mouse models and human patients are not well understood. Specifically, it is unclear why ventral and central cones in mouse models die much more rapidly than dorsal cones. Similarly, it is unclear why blue cone function is lost early in patients. The objective of this application is to define the mechanism responsible for the rapid cone degeneration in LCA using the Lrat-/- model. Our central hypothesis is that cone opsin determines the rate of cone photoreceptor degeneration in LCA. We formulated this hypothesis based on our preliminary data showing the short-wavelength (SW) opsins are prone to aggregation/accumulation triggering endoplasmic reticulum (ER) stress than the medium/long-wavelength opsin. In Aim 1, we will dissect the relative contributions of S and M opsin to cone degeneration in Lrat-/- mice by genetically deleting S-opsin or M-opsin. In Aim 2, we will determine the structural basis on why chromophore deprivation causes S-opsin but not M-opsin aggregation. We identified a phenylalanine-rich region in the short-wavelength opsin family (SW1) but absent from the medium/long-wavelength opsin family. Since aromatic residues play a significant role in the aggregation of proteins by directing self-assembly via ¿-¿ interactions, we hypothesize that the phenylalanine-rich region in the S-opsin is responsible for its aggregation in Lrat-/- cones. We designed two sub-aims to test this hypothesis. Sub-aim 2A; swap the phenylalanine-rich region in the S-opsin (70-125) with the homologous region of M-opsin (86-141) by gene targeting. Sub-aim 2B, inhibit S-opsin aggregation with N- (1, 4-dihydro-1, 4-dioxo-2-naphthalenyl)-L-tryptophan (NQTrp) by disrupting the ¿-¿ interactions between the phenylalanine-rich region. We expect these studies will define the mechanism on why S-cones degenerate faster than M-cones in RPE65/LRAT-LCA. PUBLIC HEALTH RELEVANCE: These studies will define the mechanism on why S-cones degenerate faster than M-cones in RPE65/LRAT- LCA. The proposed mechanism that cone opsin aggregation is responsible for rapid cone degeneration can be exploited in designing novel therapeutic agents in the treatment of LCA. For example, NQTrp has the potential to serve as a lead for developing a new class of therapeutic drugs for LCA by blocking cone opsin aggregation.
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1 |
2014 — 2016 |
Fu, Yingbin |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Mechanisms and Treatment Strategies For Polypoidal Choroidal Vasculopath
DESCRIPTION (provided by applicant): Polypoidal choroidal vasculopathy (PCV) is characterized by a network of branching vessels with terminal polypoidal dilations in the choroid. PCV, which is also considered a variant of occult choroidal neovascularization (CNV), can lead to recurrent serous exudation and subretinal hemorrhage. We recently reported the generation of the first PCV model by transgenically expressing human HTRA1, a multi-functional serine protease, in mouse retinal pigment epithelium (RPE). We showed that increased HTRA1 induced characteristic features of PCV, including branching networks of choroidal vessels and polypoidal lesions. Transgenic hHTRA1+ mice also developed occult CNV. Ultrastructural study revealed degeneration of both the elastic lamina and tunica media of choroidal vessels, as well as the degradation of the elastic lamina of Bruch's membrane in hHTRA1+ mice. These results suggest that HTRA1-mediated degradation of extracellular matrix (ECM) proteins in the RPE-choroid region is responsible for its pathological role in PCV. The objectives of this project are: 1) to use our hHTRA1+ mouse model to define the pathophysilogical steps between HTRA1 expression, proteolysis of ECM proteins, and progression of PCV; 2) use our knowledge from this model to design a new PCV-treatment strategy. The Specific Aims are: (1) Test the hypothesis that PCV is caused by HTRA1 mediated degradation of ECM proteins in the RPE-choroid region through its proteolytic activity. (2) Test the hypothesis that following the initial assault by HTRA1- that is, ECM protein degradation - inflammatory processes are involved in the progression of PCV. (3) Develop a new strategy for treatment of PCV by inhibiting the proteolytic activity of HTRA1.
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