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ARRA Investments in Cataract

Public Health Burden
Cataract is a leading cause of blindness worldwide. In cataract, the ocular lens loses its natural transparency, becomes opaque or cloudy, and thereby prevents the light from reaching the photo-receptive region of the eye -- the retina. Globally, it is estimated that around 20 million people are bilaterally blind due to cataract. In the United States, and by age 80, more than half of all Americans have either cataract or have had cataract surgery. Indeed, cataract surgery is one of the most common operations performed in the US. This in turn is associated with significant cost. In 1998 alone, more than 1.3 million cataract operations were performed in the USA at a cost of $3.5 billion dollars. Furthermore, while the majority of cataract cases are age related -- cataract can be congenital and can result in even more devastating and long lasting effects.

In advanced stages, cataract treatment involves performing surgery on the affected lens (most usually phacoemulsification) where a very small incision is made through the cornea, the lens is emulsified, extracted, and then replaced with an artificial intraocular lens (IOL). While cataract surgery is highly successful and is associated with relatively low incidence of post-operative complications – a fairly common development is the so-called posterior capsular opacification (PCO) where new lens cells grow over the IOL and need to be subsequently removed through laser therapy.

Basic and Clinical Research:
Over the years, investigators have made several important findings on the physiology and pathophysiology of the lens. For example, development of the lens through a process called lens induction is fairly well understood and serves as a model of understanding the general process of tissue induction. Moreover, NIH supported research has identified several tantalizing clues to the potential etiology of cataract. Whether oxidative stress, protein aggregation, disruption of chaperone activity, or more generally, homeostatic dysregulation of the lens – each model is currently being studied and pursued in its relation to cataract development.

In order to capitalize on these important clues to cataract – NIH ARRA funds were used to further support basic and clinical research:
  • Study the initiation and growth of protein aggregates in living animals using non-invasive methods. This is especially important given the key role of protein misfolding and aggregation in cataract. 1
  • Analyze the genetic and epigenetic regulatory elements of the alpha-A crystallin in the ocular lens. Alpha-A crystallin is the most abundant crystallin in the lens. It also has one of the most important non-refractive functions identified for a crystallin – namely chaperone function. A detailed understanding of the regulation and expression of aA crystallin is therefore critical.2
  • Understand further the mechanistic roles of gap junctions in cataract formation. By focusing on a critical gap junction component - Connexin 50 - this project tackles an important clue in cataract development: homeostatic dysregulation and osmotic stress.3
  • Determine the key molecular requirements for methionine sulfoxide reductase (MsrA) repair of alpha-crystallin chaperone activity. This project ties in nicely with two key themes in cataract research: oxidative stress (including antioxidant responses) and chaperone activity of alpha crystallins.4
  • Examine the contribution of the small heat shock proteins a-crystallins to lens transparency and define their roles in cataract. This project will use state-of-the-art biophysical methods to investigate the protein-protein interactions that are hypothesized to play a key role in cataract in particular, and in protein-misfolding diseases in general.5
  • Investigate the effects of aging and oxidative damage in the development of age-related and x-ray caused cataract. An advantage of this work is its tackling of age-related cataract which is by far the most prevalent cause of cataract incidence.6
  • Identify and characterize genetic mouse models of cataract. This work isolates specific mutations in the mouse that result in cataract development and then proceeds to identify the molecular pathways  in which these genes are involved. A strength of this project is that it has the ability to identify novel genes correlated with or potentially causative of cataract.7
Summer Students Supplements:
  • Two other administrative supplements under ARRA were awarded to hire undergraduate summer research students and directly involve them in lens and cataract research. These summer student supplements were awarded to Oakland University in Michigan, and the University of Delaware.

  1. 3R01EY004542-27S1; Development and Maintenance of Lens Cell Transparency; Seattle, WA (PI: John Clark).
  2. 3R01EY014237-07S1; Transcriptional control of the mouse aA-crystallin locus; New York, NY (PI: Ales Cvekl).
  3. 3R01EY012085-11S1; Intracellular Communication in the Eye Lens; San Antonio, TX, (PI: Jean Jiang).
  4. 3R01EY013022-10S1; Molecular Analysis of Microdissected Cataractous Human Lenses; Boca Raton, FL (PI: Marc Kantorow).
  5. 3R01EY012018-12S2; Molecular Basis of Lens Transparency; Nashville, TN (PI: Hassane Mchaourab).
  6. 3R01EY011733-10S1; Dietary and Genetic Control of ROS Damage to the Lens; Seattle, WA (PI: Norm Wolf).
  7. 3R01EY015173-05S1; Visual Genetic Studies on Models of Nuclear Cataracts; Milwaukee, WI (PI: D.J. Sidjanin)

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