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The Kelly Group

A central theme of our research is to understand the chemistry and biology of protein homeostasis (proteostasis) and the influence of proteostasis pathways on 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 proteostasis network within the cell pharmacologically to enhance the folding and trafficking or clearance of aggregation-prone and/or misfolding-prone proteins. Proteostasis 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 led 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 nervous systems 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
  • Developing and optimizing peptide probes to quantify non-amyloid aggregates in patient plasma or CSF
  • Understanding the mechanism of proteotoxicity in the transthyretin amyloidoses using C. elegans models, in collaboration with the Encalada Lab
  • Understanding the mechanism of proteotoxicity in amyloid diseases using human patient-derived cells
  • Discovering small molecule activators of stress-responsive signaling pathways, e.g., ATF6 activators
  • Discovering small molceule autophagy activators
  • Understanding and ameliorating light chain amyloidosis
  • Developing light chain kinetic stabilizers
  • Understanding the thermodynamic and kinetic effects of N-glycosylation on protein folding in vitro and in the cell
  • Understanding how the cell maintains gylcoproteostasis
  • Development of the Inverse Drug Discovery strategy
  • Alleviating lysosomal storage diseases by manipulating cellular proteostasis
  • Theoretical and experimental characterization of the proteostasis network in E. coli
  • Understanding and ameliorating gelsolin amyloidosis
  • Understanding and alleviating age-related macular degeneration
  • Developing and optimizing a kinetic aggregation assay to quantify amyloid load in tissues and biological fluids
  • 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
Mail: BCC265
Tel: (858) 784 9880
Fax: (858) 784 9610