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Overview Of Research

Understanding the principles underlying CELLULAR QUALITY CONTROL — the integration of processes by which the cell senses, responds and adapts to environmental and physiological challenges — is among the most fascinating problems in biology. The appearance of incorrectly expressed or improperly folded proteins results in a cellular stress response involving activation of stress-induced transcription factors and leads to the elevated expression of molecular chaperones and proteases that serve to clear damaged proteins.

An imbalance in protein homeostasis results in the accumulation of misfolded and aggregation-prone proteins that are poorly refolded and degraded, often accumulating as oligomeric intermediate species and aggregates in different subcellular compartments. These events are hallmarks of human genetic diseases including the polyglutamine-expansion diseases such as Huntington's disease, Parkinson's disease, Alzheimer's disease, familial ALS, prion diseases, amyloidosis, cystic fibrosis, and a-1-antitrypsin disease. This has led to increased interest in the toxicity and pathogenesis of misfolded proteins and the role of protein aggregates in cellular dysgenesis.

Our laboratory is interested in the fundamental events that underlie the appearance of misfolded proteins and their consequence to protein homeostasis, cellular function, and organismal adaptation and survival. Current areas of research are:

Transcriptional regulation of heat shock response involving the molecular response to environmental and physiological stress, the regulation of a family of heat shock transcription factors (HSFs) during development and aging and their roles in stress-induced transcriptional regulation of genes encoding heat shock proteins and molecular chaperones.

A mechanistic understanding of the roles of molecular chaperones (how they move between subcellular compartments) in protein folding and trafficking, and as stress sensors in cell growth and death, specifically how Hsp70 and Hsp90 associate with co-chaperones including Bag1, J-domain and TPR-domain proteins as "stress sensors" at the interface of molecular decisions between cell stress and decisions for cell growth or cell death.

The goal of the all chaperome project, is to characterize the molecular chaperones of C. elegans. Identification of the chaperones expressed in specific tissues will provide a basis for high throughput and biochemical studies to establish the chaperone interactome.

Molecular events associated with the expression of misfolded and aggregation-prone proteins in neurodegenerative diseases: how aggregation-prone proteins form alternate misfolded species; on the formation, biogenesis, and dynamics of aggregate formation and interaction with cellular proteins, genome-wide screens and analyses of genes that define the "protein folding proteome"; and on the dynamic interplay with chaperone networks and the degradative machinery.

C. elegans as a model system for analysis of stress response and diseases of protein misfolding. Using genome-wide tools including microarray analysis, bioinformatic analysis, interference RNA and screening for mutants defective in stress pathways to obtain a comprehensive understanding of the molecular response of cells and tissues in C. elegans to environmental and biochemical stresses including heat shock, osmotic stress, misfolded proteins, and chemical and oxidative stressors.

Small molecule screening for the stress response including for pharmacologically active candidate drugs that regulate the heat shock response and the activities of molecular chaperones using both C. elegans and human cells expressing various heat shock reporter constructs to identify promising small molecules that can be developed further as modulators of the heat shock response or gene-specific regulation of heat shock genes.

The genetic networks that determine how an organism detects and responds to stress form a dynamic and complex system. Exposure to stress causes a perturbation of this system as the organism prepares a defense against its changing environment. Recent developments in methodologies provide us with powerful tools in our systems approach to cell biology for extracting meaning from a variety of stress response networks.

Transcriptional regulation of heat shock response
Roles of Molecular Chaperones in Protein Folding, Trafficking, and Stress Sensors in Cell Growth and Death
All Chaperome Project
Misfolded and aggregation prone proteins in neu
C elegans as a model system for analysis of stress response and diseases of protein misfolding
Small molecule screen for the stress response
Systems Approach to Stress Biology