Larry David, PhD

Dr. Larry DavidCataracts result from opacification of the normally clear lens of the eye.  Since cataracts are a leading cause of blindness, studies determining the cause of cataract are an active area of vision research.  Our interest is in the changes occurring in the structural proteins of the lens when cataracts form.  These structural proteins are called crystallins.  Crystallins are some of the oldest proteins found in the body, since those found in the center of our lenses were synthesized before birth and remain with us for our entire lives.  Due to their age, these proteins undergo extensive modifications, including cleavage, deamidation, racemization, isomerization, and oxidation. The challenge in this research is to distinguish between normal age-related modifications and unique modifications causing cataract.  To make this distinction, my group analyzes the structure of crystallins using mass spectrometry.  Measurement of the molecular mass of the crystallins and their peptides allows an unambiguous identification of their modifications.  Once the modifications unique to crystallins from cataractous lenses are known, it will be possible to model how the alterations cause these proteins to aggregate and cause cataract.  This information will be used to help develop agents to slow cataract formation. 

Current methodologies include probing changes in crystallin structure by measuring hydrogen/deuterium exchange rates; high-resolution data-independent tandem massspectrometry to detect deamidation, isomerization, and racemization at asparticacid and asparagine residues; mapping of non-native disulfide bonds; and quantitative analysis of protein aggregates in lens using stable isotope labeled crystallin standards.  Our laboratory is also affiliated and next door to the university wide proteomics shared resource that is equipped with Orbitrap Fusion and Q-Exactive HF mass spectrometers.  This facility is partially supported by NIH Vision and Cancer core grants and provides a fertile training ground for students interested in proteomics research.

Link to NIH Biosketch