Pathology’s Parameswaran Ramakrishnan issued patent

Parameswaran Ramakrishnan, assistant professor of pathology, and David Baltimore of the California Institute of Technology, were recently issued a patent titled “Targeting c-Rel O-GlcNAcylation and Uses Thereof.”

The research

Type 1 diabetes is an incurable autoimmune disease, where a type of white blood cells, T cells, become self-reactive and attack insulin-producing beta cells in the pancreas. This leads to hyperglycemia and several associated secondary complications. T regulatory cells, another type of T cells, are necessary to suppress the self-reactivity or unwanted activity of T cells. The transcription factor, nuclear factor kappaB subunit, c-Rel protein, is required for the function of these two different types of T lymphocytes that has opposing function. C-Rel is critical in regulating both overlapping and distinct set of genes in these T cell types and a delicate balance of this gene expression controls normal T cell functions. Any change in c-Rel function in T lymphocytes, due to the environment or due to a disease condition, can change the balance of the function of different subsets of T cells, either exacerbating or blocking a disease state.

The researchers found that hyperglycemic conditions, such as that in diabetes, uniquely modifies c-Rel protein by attaching a sugar, N-acetyl glucosamine, to it in a process called O-GlcNAcylation, and changes it activity.

Sugar modification of c-Rel alters the function of c-Rel in autoimmune diabetes, in two ways:

  • It promotes the activity of proautoimmune T cells; and
  • Suppresses the activity of immunosuppressive T regulatory cells.

The combined effect of these opposing functions generates a condition that accelerates the progress of autoimmunity.

In addition to cellular systems and mouse model, the researchers also found that c-Rel is highly modified by O-GlcNAcylation in T cells of patients with diabetes.

Therefore, targeting c-Rel O-GlcNAcylation, by developing agents that specifically block the function of sugar-modified c-Rel will prove and effective strategy to control autoimmunity in type 1 diabetes.

Learn more about the patent.