Maintaining and regulating protein synthesis, folding, secretion/trafficking and degradation is crucial to ensure organismal integrity and is a fundamental challenge for all cells, especially upon aging. The cell’s ability to accurately control the protein-based system which regulates the fate of the proteome, termed the protein homeostasis network, keeps individuals free from protein misfolding and aggregation-linked diseases. Dysfunction of cellular protein homeostasis during aging significantly contributes to prevalent degenerative diseases including Alzheimer’s disease, Parkinson’s disease, and age-related macular degeneration.
The overarching goal of research in the Hulleman Lab is to identify and pursue challenging, poorly characterized biological problems with broadly-translatable implications for the treatment of protein misfolding diseases. Specifically, we aim to develop an understanding of the fundamental cellular and molecular mechanisms which underlie age-related and inherited diseases with an emphasis on disorders caused by secreted and extracellular matrix (ECM) proteins.
We employ a multi-disciplinary approach combining chemical biology, cellular/molecular biology and biochemistry to understand the pathophysiological consequences of altering the cellular protein homeostasis network in the context of aging and disease. Then, using this newly-gained knowledge of disease biology, the Hulleman Lab employs both rational and unbiased drug discovery approaches to identify and validate novel routes of therapeutic intervention.
The broad hypothesis that we test is that we can treat age-related and inherited protein misfolding diseases by pharmacologically and/or genetically adapting the protein homeostasis network. As a proving ground for this endeavor, the Hulleman Lab focuses its attention on a series of age-associated as well as inherited ocular disorders.
The eye is a unique, therapeutically tractable organ which is exquisitely sensitive to age-related cellular perturbations such as exposure to environmental stresses, increases in oxidative stress, and protein folding challenges. For these reasons, we embrace the eye as a window to view the nuances of aging and as a testing ground for strategies to therapeutically promote protein homeostasis systemically within the body. We anticipate that results from our eye-based studies will be applicable to numerous other degenerative diseases caused by protein misfolding and compromised protein homeostasis.