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ARRA Investments in Ocular Angiogenesis

Public Health Burden
Ocular angiogenesis plays an important role in many major eye diseases.  Abnormal blood vessel growth in retinal vascular diseases, such as Diabetic Retinopathy (DR), retinopathy of prematurity (ROP) and the wet form of Age-related Macular Degeneration (AMD), would lead to blindness if not controlled. Avascularity of the cornea is necessary for optical transparency in the visual axis. The cornea has been used as a platform for testing the efficacy of anti-angiogenic therapies for use in cancer, macular degeneration and diabetes.  Abnormal cornea angiogenesis can also lead to blindness.  Visual loss has important psycho-social and economic impact in the United States, and understanding the underlying pathologic mechanisms, preventing and treating blindness remain important goals for vision research.

Despite the use of recently approved molecular therapeutics targeting vascular endothelial growth factor (VEGF)-A, the majority of patients do not recover good, functional vision, and a significant fraction progress to legal blindness. In retinal diseases, choroidal neovascularization (CNV) progresses to invade the retina and causes structural and functional tissue damage. Therefore, effective treatment remains elusive for many patients with retinal diseases. Also, uncontrolled cornea angiogenesis triggered by infection and other diseases can lead to blindness, and this group of patients has a higher rejection rate for corneal transplantation. A variety of ARRA funded grants are exploring potential new treatments.  A few include:
  • Targeting gamma-secretase activation for anti-angiogenesis.1
  • Developing new technologies that can detect and treat CNV in its earliest stage.2
  • Testing the hypothesis that retinal neovascularization is facilitated by the expression of specific growth factors, extracellular proteinases, and their inhibitors, the inhibition of which may lead to new and useful therapies.3
  • Employing animal models to test if the very low-density lipoprotein receptor (VLDLR) functions as a negative regulator of CNV, and whether the regulatory effect of VLDLR, a wnt co-receptor, is through the wnt pathway.4
  • Identifying a new nutritional and pharmacologic intervention to prevent diabetic and other retinopathy, with a focus on lipid based molecules which act as effectors of inflammation and angiogenesis.5
  • Applying RNA interference, a promising new efficient & specific molecular technology that targets specific mRNAs, to elucidate mediators and mechanisms of normal corneal avascularity.6
  • Developing an efficient, safe clinical treatment for diabetic retinopathy using stem cells from the patient's bone marrow or blood that have been activated to repair damaged vessels in the eye.7
Basic Research
To lay the basis for future vascular eye diseases treatments, NIH ARRA funds also support basic investigations.
  • Understand how the immune system may play a role in initiating and sustaining aberrant angiogenesis in the eye.8
  • Determine how a specific cytochrome P450 (CYP1 B1) and its metabolites regulate retinal vascular homeostasis.9
  • Study the role of astrocytes in the establishment of a functional retinal vasculature. 10
  • Gain an understanding of the mechanism(s) by which TIMP-3 and its mutations regulate choroidal neovascularization.11

  1. 3R01EY018358-04S1 -- Targeting gamma-secretase activation for anti-angiogenesis -- Boulton, Michael Edwin (FL)
  2. 1RC1EY020442-01 -- CCR3: a molecular marker for neovascular AMD --Ambati, Jayakrishna (KY)
  3. 3R01EY012604-11S1 -- Extracellular Proteinases in Ocular Neovascularization --Das, Arup (NM)
  4. 1R01EY018659-01A1 -- The wnt signaling pathway in choroidal neovascularization --Ma, Jian-Xing (OK)
  5. 3R01EY017017-04S1 -Dietary control of angiogenesis in retinopathy model; basis for clinical trials -- Smith, Lois (MA)
  6. 3R01EY017950-02S1 -- The Role of sFlt in Corneal Avascularity -- Ambati, Balamurali (KY)
  7. 1R43EY020030-01 -- Autologous TGF-B-Modified HSC for Repair of Vasodegenerative Diabetic Retinopathy- Bartelmez, Stephen Hollis (CA)
  8. 3K08EY016139-04S1 -- Immune Mechanisms in Choroidal Neovascularization. Apte, Rajendra S (MO)
  9. 1R01EY018179-01A2 -- CYP1B1 and Retinopathy of Prematurity. Sheibani, Nader (WI)
  10. 1R01EY018636-01 — A Crystallin Mutation with Abnormal Astrocytes and Retinal Vessels. Sinha, Debasish (MD)
  11. 3R01EY016490-04S1 -- Role of TIMP-3 in Ocular Neovascularization, Anand-Apte, Bela (OH)

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