Dr. Chandrasekharappa's research focuses on the development and use of genome technologies to advance research in human genetics. For more than a decade, he has been involved in the large-scale mapping and positional cloning of disease genes, with particular emphasis on the genes responsible for Alagille syndrome (AGS) and multiple endocrine neoplasia type 1 (MEN1).
AGS is a congenital disorder characterized by fewer bile ducts than normal in the liver and abnormalities of the heart, eyes, vertebrae, and face. Thus, multiple organ systems are affected, but the extent to which each is affected varies from individual to individual. MEN1 is a rare hormonal disorder also known as multiple endocrine adenomatosis or Wermer┐s syndrome. In MEN1, hormone-producing glands develop multiple tumors. The affected glands in MEN1 are primarily the parathyroid, pituitary, and pancreas; in many individuals, all three are affected. Although the symptoms may vary, they are often severe. For example, an overactive parathyroid gland can produce excess calcium in the blood, leading to kidney damage. A hyperactive pituitary gland can produce an array of symptoms, including infertility and excessive growth. A hyperactive pancreas can promote severe ulcers in the stomach and intestine, and some of these tumors may become cancerous.
Dr. Chandrasekharappa and colleagues discovered the genes responsible for both disorders in 1997. AGS is caused by mutations in the human JAG1 gene, which encodes a ligand (JAGGED 1) for the Notch transmembrane receptor. The Notch signaling pathway, originally discovered in fruit flies, is important in determining the early fate of the cell. MEN1 is caused by mutations in the tumor suppressor gene, MEN1. This gene encodes a protein called menin, which is expressed very early in development, resides in the cell nucleus, and appears to bind several different proteins including the transcription factor JunD. When bound to menin, JunD represses cell growth; without menin, JunD promotes cell growth.
The basic biological function of menin is not entirely clear. However, it is known that the JAGGED 1 protein is involved in various developmental processes. A total loss of menin is needed to cause tumors in MEN1 patients, whereas a partial loss of the JAGGED 1 is sufficient to cause AGS. One of the major activities of Dr. Chandrasekharappa's laboratory is studying the function of both proteins, particularly to understand how their loss leads to the respective diseases. These efforts include developing a model of AGS in zebrafish and models of MEN1 in fruit flies, zebrafish, and mice.
Dr. Chandrasekharappa often collaborates with other scientists to locate and clone human disease genes. His expertise in the applications of genomic technologies to positional cloning has led to collaborations with scientists interested in defects in zebrafish development. He also is working on adapting microarray technology to a new use: searching for chromosomal alterations or deletions that might be involved in many human diseases. Microarrays traditionally have been used for detecting gene expression changes in particular tissues. However, if stretches of genomic DNA are used, the microarray can detect chromosomal deletions or amplifications in cancer cells. Dr. Chandrasekharappa believes such higher-resolution searches for potential genomic alterations might pay off by detecting chromosomal changes in a number of diseases whose molecular defects have not yet been characterized.
Top of page
Last Updated: May 18, 2014