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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 comprising the proteostasis network; including ribosomal protein quality control, chaperone (chaperonin) and enzyme-mediated folding vs. proteasome- and autophagy-mediated degradation. Knowledge gained from our mechanistic investigations is used to conceive of new small molecule 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 - characterized by degeneration of the peripheral nervous system and/or the heart. We are also currently developing novel therapeutic strategies  for degnerative diesases including Alzheimer's and Parkinson's diseases, and for loss-of-function diseases such as the lysosomal storage diseases.

We currently collaborate with the Baldwin, Cravatt, Encalada, Sharpless, Wilson, Wiseman, Wong, and Yates 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, in collaboration with the Encalada Lab
  • Discovering stress-responsive signaling pathway small molecule activators
  • Discovering autophagy pathway small molecule activators
  • Developing and optimizing a kinetic aggregation assay to quantify amyloid load in tissues and biological fluids
  • Developing and optimizing peptide probes to quantify non-amyloid aggregates in patient plasma or CSF
  • Understanding the mechanism of proteotoxicity in amyloid diseases using model organisms
  • Understanding and ameliorating light chain amyloidosis
  • Alleviating lysosomal storage diseases by manipulating cellular proteostasis
  • Understanding and ameliorating gelsolin amyloidosis
  • Understanding and alleviating age-related macular degeneration
  • Theoretical and experimental characterization of the proteostasis network in E. coli
  • Developing small molecule ATF6 activators and inhibitors
  • Developing small molecule IRE1 activators and inhibitors
  • Understanding the thermodynamic and kinetic effects of N-glycosylation on protein folding in vitro and in the cell
  • 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