Modulation of Corneal Wound Healing using Pre-Surgical Dietary Restriction

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 DESCRIPTION (provided by investigator): Dietary restriction (DR), defined as reduced food intake without malnutrition, has been shown to extend lifespan in a wide variety of organisms, as well as provide increased resistance to many forms of acute stress. While most studies have focused on ischemia reperfusion injury to the brain, heart, kidney and liver, DR has also been shown to improve survival and hepatic regeneration following non-ischemic liver resection surgery, and to reduce fibroblast proliferation and extracellular matrix synthesis during dermal wound healing. These results, along with gene expression data from other tissues, suggest that DR may have the potential to improve post-surgical ocular wound healing responses by reducing cell death, inflammation and fibrosis; however, this has not yet been directly or quantitatively assessed. Since it is directly exposed to the environment, the cornea is susceptible to physical trauma, chemical injury and infection. Corneal scarring, which can develop in response to these insults, is a leading cause of blindness worldwide. Because of its accessibility and optical power, the cornea is also the target for vision correction procedures such as photorefractive keratectomy (PRK) and LASIK - with over 500,000 procedures performed annually in the US. The development of corneal haze due to stromal fibrosis remains a significant complication in a subset of these patients. The goal of the proposed research is to perform an initial assessment of the effects of DR on corneal wound healing at the cellular level by: 1) Using in vivo confocal imaging to assess the effects of both long-term DR and short term fasting on changes in corneal epithelial and stromal thickness, keratocyte density, and cell and ECM backscattering after mechanical debridement or transcorneal freeze injury in the mouse; and, 2) Using in situ imaging, immunocytochemistry and biochemical assays to directly correlate these clinical outcome measurements with differences in initial cell death, inflammation, expression of pro-inflammatory cytokines, and the expression and localization of markers for myofibroblast transformation and fibrosis. The proposed research will be the first to determine whether long-term dietary restriction or short-term fasting results in reduced corneal fibrosis following injury. These exploratory studies could ultimately lead to the identification of new targets and mimetics for mitigating the loss of corneal transparency (and thus visual acuity) that can occur following injury or refractive surgery. Because the primary mediators of wound healing and fibrosis in the cornea are the same as those in most other tissues, information gained in these studies should also provide insights into the potential impact of DR on post-surgical wound healing throughout the body. During the course of the grant, training will be provided to one biomedical engineering graduate (Ph.D.) student, one post-doc, as well as 2 summer medical students and 2 undergraduate research fellows.