Human Disease and Therapeutics

What is Human Disease and Therapeutics? 

Fundamental changes in proteins and nucleic acids underlie many human diseases. These can be alterations in sequence, structure or modification of a critical protein (such as glycosylation or methylation), or changes in the regulation or expression levels of biological macromolecules within the cells. Human pathogens often possess unique macromolecules whose role is critical to the pathogens survival. Many recent therapeutics were discovered, using of screening and structure based drug design methodologies, through understanding the molecular mechanism by which biological macromolecules function. However, in cancer and pathogens, these discoveries can be undermined by rapid evolution causing drug resistance. 

Our research in the area of Human Disease and Therapeutics

In BMP we take a molecular approach to elucidating the molecular mechanisms that underlie many human diseases.  Often these approaches involve distinguishing how the disease state alters the mechanism of action of a normal human protein or level, either due to mutation or expression level. We leverage a combination of biochemistry, molecular biology, enzymology, bioinformatics, structural biology and chemical synthesis to elucidate the mechanisms that cause disease and design novel therapeutics. The diseases our faculty focus on include:  congenital diseases due to mutations (including many neurodegenerative diseases such as ALS), diabetes, cancer and diseases involving changes to the immune response and infectious diseases. 

The role of mutations that lead to disease are studied by: the in oligosaccharyltransferase subunits in the family of diseases known as congenital disorders of glycosylation; the Kobertz laboratory investigates how mutations that prevent N- and O-glycosylation give rise to fatal cardiac arrhythmias; The Matthews laboratory studies mutations in Superoxide dismutase with the who studies mutations in Profilin and TDP-43 all associated with ALS; The Weng laboratory, as part of the psychENCODE consortium, develop and apply computational genomic methods to study psychiatric disorders; And the Munson lab studies how mutations in endocytic regulatory proteins lead to neutrophil dysfunction, bone marrow failure, and neurological disorders.

In cancer and inflammation we are often impacted by subtle changes in the regulation and expression of key enzymes: the Kelch laboratory is studying the DNA replication and repair machinery of humans; the Royer laboratory are investigating the activation and designing of inhibitors for proteins involved in cancer (CtBP) and autoimmune disease (IRF5); the Schiffer laboratory are studying the cytidine deaminase APOBEC3 enzymes and the Thompson laboratory is developing therapeutics targeting a series of arginine modifying enzymes, including the Protein Arginine Deiminases (PADs). 

In infectious diseases, the Schiffer laboratory studies the molecular basis for drug resistance and the design of new inhibitors that are less susceptible to resistance for the viral proteases: HIV, Hepatitis C, Dengue and Influenza neuraminidase. The Bolon lab also studies the evolution of drug resistance in Influenza and HIV.

Our breakthrough discoveries 

Impact of Mutations:

  • The Gilmore laboratory discovered that mutations in the active site subunits, STT3A and STT3B, cause . 
  • The Kelch laboratory discovered the molecular basis for a rare inherited .

Cancer and Inflammation:

  • The Royer laboratory has identified the to date against the cancer target CtBP, which contributes to a broad range of cancers.  Discovered (and other family members) are activated upon phosphorylation and are developing inhibitors to disrupt the activated form, which has been linked with autoimmune diseases, particularly lupus.
  • The Thompson lab developed the first inhibitors targeting the PADs, a class of enzymes that play an active role in the development and progression of rheumatoid arthritis and other autoimmune diseases, leading to the formation . 

Infectious Diseases

  • The Schiffer laboratory discovered molecular mechanisms by that drug resistance is conferred via mutations by altering the balance between substrate recognition and inhibitor binding. They that successfully avoid drug resistance. 

Our PIs that are conducting research in the area of Human Disease and Therapeutics


C. Robert Matthews

Anthony Imbalzano

Brian Kelch

William Kobertz

Nese Kurt Yilmaz

Elisabet Mandon

Francesca Massi

Mary Munson

William Royer

Celia Schiffer

Zhiping Weng