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The Kelly Group



The central theme of our research is to understand the chemistry and biology of protein folding and the competition between protein folding, misfolding and aggregation, the latter two processes being associated with a spectrum of human diseases. A recent focus has been on adapting the innate biology of protein maintenance carried out by the protein homeostasis, or proteostasis, network within the cell to enhance the folding and trafficking or clearance of aggregation-prone and/or misfolding-prone proteins. Protein maintenance is influenced by the energetics of protein folding, misfolding and aggregation as well as by numerous regulated networks of interacting and competing biological pathways; including ribosomal protein synthesis, chaperone (chaperonin) and enzyme-mediated folding, vesicular trafficking, disaggregation, and proteasome- and autophagy-mediated degradation pathways. Knowledge gained from our investigations is used to conceive of new therapeutic strategies that in one case have lead to the discovery of a first-in-class small molecule drug for the amelioration of gain-of-toxic-function transthyretin amyloid diseases that result in degeneration of the peripheral nervous system and/or the heart. We are also currently developing novel therapeutic strategies based on our basic research for Alzheimer's disease and for loss-of-function diseases such as Gaucher disease and related lysosomal storage diseases.

We currently collaborate with the Balch, Dillin, Wiseman, Wilson, Ron, Yates, Wong and Buxbaum Laboratories.

Ongoing projects in the Kelly Laboratory include:

  • Developing second generation transthyretin kinetic stabilizers
  • Understanding the mechanism of proteotoxicity in the transthyretin amyloidoses using C. elegans models
  • Characterizing the molecular underpinnings of the amyloid fibril disaggregase activity in mammals
  • Developing and optimizing a kinetic aggregation assay to quantify amyloid load in tissues and biological fluids
  • Understanding the mechanism of proteotoxicity in Alzheimer’s disease using model organisms
  • Understanding and ameliorating gelsolin amyloidosis
  • Understanding and alleviating age-related macular degeneration
  • Understanding and alleviating light chain amyloidosis
  • Ameliorating lysosomal storage diseases by manipulating cellular proteostasis
  • Theoretical and experimental characterization of the proteostasis network in E.coli
  • Developing small molecule IRE1 activators and inhibitors
  • Thermodynamic and kinetic effects of glycosylation on protein folding in vitro and in the cell
  • Understanding β-sheet folding in vitro and in cells
  • Delineating the role of metabolite-initiated protein aggregation in human amyloid diseases
  • Development of protein folding and aggregation sensors that function in cells and organisms

For a more detailed overview of our laboratory with a historical perspective, click here.

10550 North Torrey Pines Road
La Jolla, California 92037
USA
Mail: BCC265
Tel: (858) 784 9880
Fax: (858) 784 9610
E-mail: jkelly@scripps.edu