Biochemistry/Organic Chemistry
Photo Catherine GrimesCatherine L. Grimes, Assistant Professor

(302) 831-2985 • cgrimes@UDel.Edu • http://www.udel.edu/chem/grimes/

(b. 1978) B.A., 2001, Villanova University; M.A., 2003, Princeton University; Ph.D., 2006, Harvard University; Postdoctoral, 2006-2011, Harvard University

Current Research

The Grimes lab is generally interested in understanding how mammalian cells recognize and respond to the presence of a pathogen. We take a chemical biological approach to investigate this problem, utilizing a host of tools such as organic synthesis, molecular biology, biochemistry and bacterial cell engineering.

We study the activation of the innate immune system by a bacterial threat. The innate immune system is the body's first line of defense against invading pathogens. This ancient system has evolved to live in a symbiotic relationship with some commensal bacteria and at the same time recognize and destroy virulent bacteria. Understanding the molecular details of this system is extremely important, as chronic inflammatory disorders, such as Inflammatory Bowel Disease, arise from an inappropriate immune response to bacteria.

Synthesis of Small Bacterial Cell Wall Fragments

The bacterial cell wall, a peptidoglycan, is a highly conserved structure found in all bacteria. The peptidoglycan is a mesh-like carbohydrate polymer that provides the mechanical support necessary to prevent the cells from bursting as the osmotic pressure fluctuates. Humans do not have bacterial cell walls and thus it makes an ideal structure for our innate immune systems to recognize the presence of bacteria. It has long been known that small fragments of bacterial cell wall, such as muramyl dipeptide (see Figure 1) are able to stimulate an immune response. In order to identify the receptors of these molecules, we use chemical synthesis to construct a variety of probes. The ability to design and synthesize a host of immunostimulatory molecules with a variety of functionality gives us a set of unique tools to dissect innate immune signaling.

Figure 1

 
Synthesis of Large Bacterial Cell Wall Fragments
We use a combination of chemoenzymatic synthesis and bacterial engineering to prepare larger fragments of bacterial cell wall. Chemoenzymatic synthesis uses a combination of chemically synthesized precursors (provided by us the chemists) and enzymes (provided by Nature) to make large, immunostimulatory fragments of cell wall. Bacterial engineering takes advantage of the bacterial cell wall biosynthetic machinery to produce unique cell walls with desired properties. We aim to synthesize unique bacterial derived biomaterials and use these to study how the human immune system processes an intact bacterial cell.
  
Intracellular Innate Immune Proteins
Scheme 1Our program focuses on a class of proteins in the innate immune system know as the Nod-Like Receptors (NLRs). These proteins police the intracellular space of the cell for bacteria and/or their traces. NLRs are called receptors and are assumed to bind bacterial derived fragments. However, no biochemical or biophysical data exist for these proposed interactions. For each NLR that we study, we ask three fundamental questions: (1): How and where are the immunostimulatory molecules of bacterial cell wall generated? (2): Do these bacterial molecules interact with a given NLR? and (3): How is the NLR activated for down-stream signaling? In order to answer these questions we make use of a variety of techniques such as protein expression, solution and solid phase binding assays and mass spectrometry.

Representative Publications