Defective Proteins and Disease
Center Leader: Yair Argon, PhD
Most diseases are caused by malfunctions of a protein. A defective receptor may preclude proper function of pancreatic cells; an altered protein may lead to malignant transformation, or the inability of a hormone to be secreted may lead to abnormal organ development. Understanding the changes in the expression or function of proteins is therefore key to developing therapies.
Gaining such understanding, however, is no small feat because each of the 30,000 genes in human DNA can encode more than one form of a protein, increasing the complexity of the information contained in DNA. In addition, not every pathologic change is due to a single gene mutation. In many diseases, the alteration is in an atypical realignment of interacting proteins.
Research conducted in the Defective Proteins and Disease Research Affinity Group focuses on this problem by investigating how proteins function, how they interact, and how they differ between normal and diseased tissues. Several investigators in the affinity group measure how receptors on the surface of cells transmit information that leads to growth and differentiation of the endocrine or the immune systems. Their work interfaces with that of another group of investigators who are interested in viral infections, since viruses often “highjack” normal cellular proteins.
Another critical area of the affinity group’s investigation lies with markers of disease, or protein patterns that are expressed differently in people with a particular disease. Some investigators are relating modifications common to many proteins, such as additions of phosphate or nitrate, to alterations in the functions of key metabolic enzymes in normal and defective neonatal development.
Yet a third focus is the question of how proteins misfold, lose their proper structure and therefore become dysfunctional. Three research groups are studying how a special set of cellular proteins, called molecular chaperones, either protect other proteins from misfolding or correct the defect, in the context of cystic fibrosis, systemic amyloidosis and thalassemia.
A new focus of the group is proteomics, cataloging all the proteins present in a given tissue at a particular stage of pathological state. Knowing these protein patterns will greatly enhance the current wealth of genetic information about a variety of diseases.
A new technique developed by the affinity group separates complex protein mixtures by multi-dimensional chromatography into hundreds of discrete fractions, and has already improved upon the enumeration of proteins that are present in diseased and normal tissues. Being able to identify rare proteins may uncover those that play important roles in an individual disease.
These research advances hold the promise of discovering signature patterns – proteins that are found consistently in patients with a specific disease – that will become diagnostic tools.
The Defective Proteins and Disease Affinity Group provides a forum for investigators from a variety of divisions to work together, improving the effectiveness of their research. Shared instruments in the Protein Core Facility, a seminar series featuring outside speakers, a monthly in-house lab meeting and a multi-investigator seed project all allow group members to interact and gain feedback on ongoing research.