Funded Research Projects

Permanent URI for this collectionhttps://hdl.handle.net/20.500.14641/189

An index of publicly funded research projects conducted by Texas A&M affiliated researchers.

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Browsing Funded Research Projects by Funding Agency "DHHS-NIH-National Eye Institute"

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    Research Project
    Evaluation of Trk Probes in Models for Dry Eye Disease
    Chemistry; TAMU; https://hdl.handle.net/20.500.14641/216; DHHS-NIH-National Eye Institute
    Evaluation Of Trk Probes In Models For Dry Eye Disease A. Project Summary In previous work, the PI designed small molecules that resemble turn regions in nerve growth factor (NGF) and in neurotrophin-3 (NT-3), for two reasons. First, ?-turn regions in the neurotrophins seem to be hot-spots for their interactions with the tropomyosin receptor kinase (Trk). Second, whereas neurotrophins activate both the Trk receptors and another receptor called p75, the small molecules should only activate the Trk receptors; this is important because activation of p75 has been associated with induction of apoptosis. In the event, several partial agonists were found, and one of them progress to phase 3 clinical trials (Mimetogen) for treatment of dry eye disease, and its fate as a pharmaceutical has yet to be decided. Most of the compounds prepared in that study, however, were not tested for applications in dry eye disease (they were just screened for properties as Trk ligands), and none of them were designed or tested for binding to TrkB (selective receptor for brain derived neurotrophic factor, BDNF). The central hypotheses of this proposal are that: (i) re-synthesis and testing of some of the original hit NGF and NT3 binding-compounds may afford other leads for treatment of dry eye disease; (ii) design principles similar to those used before could be enacted to obtain small molecule ligands that bind TrkB; and, (iii) side-by-side comparison of TrkA, B, and C probes in models for dry eye disease (cellular and in vivo) will reveal the relative impact of these compounds, and, by inference, the relative importance of stimulating those receptors in treatment of dry eye disease.
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    Research Project
    Evaluation of Trk Probes in Models for Dry Eye Disease
    Chemistry; TAMU; https://hdl.handle.net/20.500.14641/216; DHHS-NIH-National Eye Institute
    Evaluation Of Trk Probes In Models For Dry Eye Disease A. Project Summary In previous work, the PI designed small molecules that resemble turn regions in nerve growth factor (NGF) and in neurotrophin-3 (NT-3), for two reasons. First, β-turn regions in the neurotrophins seem to be hot-spots for their interactions with the tropomyosin receptor kinase (Trk). Second, whereas neurotrophins activate both the Trk receptors and another receptor called p75, the small molecules should only activate the Trk receptors; this is important because activation of p75 has been associated with induction of apoptosis. In the event, several partial agonists were found, and one of them progress to phase 3 clinical trials (Mimetogen) for treatment of dry eye disease, and its fate as a pharmaceutical has yet to be decided. Most of the compounds prepared in that study, however, were not tested for applications in dry eye disease (they were just screened for properties as Trk ligands), and none of them were designed or tested for binding to TrkB (selective receptor for brain derived neurotrophic factor, BDNF). The central hypotheses of this proposal are that: (i) re-synthesis and testing of some of the original hit NGF and NT3 binding-compounds may afford other leads for treatment of dry eye disease; (ii) design principles similar to those used before could be enacted to obtain small molecule ligands that bind TrkB; and, (iii) side-by-side comparison of TrkA, B, and C probes in models for dry eye disease (cellular and in vivo) will reveal the relative impact of these compounds, and, by inference, the relative importance of stimulating those receptors in treatment of dry eye disease.
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    Research Project
    Systemic Anti-Inflammatory Therapy to Prevent or Delay Diabetic Cataracts and Treat Post-Surgical Inflammation
    Cop - Pharmaceutical Sciences; TAMU; https://hdl.handle.net/20.500.14641/447; DHHS-NIH-National Eye Institute
    PROJECT SUMMARY Currently, surgical intervention is the only cure for cataracts, though this can be complicated in patients with diabetes. One of the most common postoperative complications in patients suffering from diabetes is persistent inflammation (uveitis) that can cause significant corneal edema, posterior synechia, and progression of diabetic retinopathy or neovascular glaucoma. There is substantial evidence that secondary cataract formation due to health conditions such as diabetes are associated with increased inflammation, oxidative stress, and sorbitol accumulation, along with covalent bonding of a protein or lipid molecule with a sugar molecule causing an increase in advanced glycosylation end products (AGE) formation that can cause significant damage to cells and tissues. The efforts to combat these effects using traditional drugs often leads to severe side effects outweighing the benefits. On the other hand natural compounds such as curcumin offer promise, but their progress is hampered due to lack of suitable dosage forms and poor bioavailability. In order to overcome inferior physicochemical and pharmacological attributes of curcumin we have prepared biodegradable nanosystems of polylactide-co-glycolide (PLGA) encapsulating curcumin (nCUR). These passively absorbed nCUR when given 8 mg/kg/day were significantly more effective than plain curcumin in delaying diabetic cataract in rodents, independent of glucose reduction. Despite the enhanced performance of passive nCUR, a significant dose remained unabsorbed in the intestine, indicating potential for further improvement through active-nanosystems. For the first time, we present a non-competitive active transport strategy to improve drug transport across biological barriers by developing carrier systems that have no equivalent in the world of competitive ligands. We hypothesize that transferrin receptor (TfR) mediated delivery across the intestinal barriers (IB) and blood ocular barriers (BOB) would significantly enhance the transport of the nanosystems making systemic anti-inflammatory therapy a reality. In this proposal, we will continue our studies on non-competitive active drug delivery strategy and understand how the systemic anti-inflammatory therapy will prevent or delay diabetic cataracts and manage post-surgical inflammation. To test this hypothesis, we propose the following specific aims: AIM #1. Establish the effectiveness of TfR in facilitating the transport of PLGA-GA NS across the IB and BOB in rat model. AIM #2. Establish the magnitude of desired or undesired effects in suitable rat models as a result of active transport. AIM #3. We will verify performance of this delivery strategy in a more man-like model. At the end of this study, we will have an effective systemic anti-inflammatory therapy to prevent or delay diabetic cataracts and treat post- surgical inflammation.