Research Project

Summary

This research program explored gene variants causing and/or modulating a number of common multigenic disorders, including Alzheimer’s, cancer (breast, endometrial, melanoma, ovarian, and prostate), inflammatory bowel disease, and osteoporosis. The research team also developed biometric and computational tools for expediting discovery of disease genes.

The group selected disorders on the basis of prevalence and morbidity, availability of large patient populations, team members’ prior knowledge, and need for and potential impact of new diagnostics and therapeutics.

Results have created knowledge relevant to medical care for a number of common debilitating diseases.  Findings include discovery of several genes and proteins involved in inflammatory bowel disease and Alzheimer’s, as well as gene variants relating to risk for a set of common cancers and metabolic bone disease.

These data provide a platform for development of tools for diagnosis of certain conditions and for identifying molecular targets for therapeutic intervention. Discoveries of genetic variants associated with such common cancers as prostate and breast have clinical implications, with all of this knowledge paving the way for predictive or diagnostic tests relating to these diseases.
In addition, this program has provided new information and methods to improve technical platforms for genotyping, gene-expression profiling, and computational management and statistical analyses of clinical and genetic datasets. Such tools are key to exploiting the human genome sequence for discovery of disease genes and, ultimately, for translating genomic information to clinical and therapeutic applications.

Fast Facts

• Highlighted outcome:  Knowledge relevant to medical care of such common debilitating diseases as Alzheimer’s, cancer (breast, endometrial, melanoma, ovarian, and prostate), inflammatory bowel disease, and osteoporosis.
• Number of research personnel:  57.
• Number of peer-reviewed publications:  16 journal articles, 20 book chapters or contributions to collective works, 23 abstracts or notes, and 109 invited presentations.
• Number of patents in process or obtained: two applications for methods for diagnosing inflammatory bowel disease and two patents relating to intestinal peptides.

Notable Publications
Chen F, Hasegawa H, Schmitt-Ulms G, Kawarai T, Bohm C, Katayama T, Gu YJ, Sanjo N, Glista M, Rogaeva E, Wakutani Y, Pardossi Piquard R, Ruan Y, Tandon A, Checler F, Marambaud P, Hansen K, Westaway D, St George-Hyslop P, and Fraser PE. 2006.  TMP21 is a presenilin complex component that modulates gamma-secretase but not epsilon-secretase activity. Nature. 440:1208-12.

Peltekova VD, Wintle RF, Rubin LA, Amos CI, Huang Q, Gu X, Newman B, Van Oene M, Cescon D, Greenberg G, Griffiths AM, St George-Hyslop PH, and Siminovitch KA. 2004. Functional variants of OCTN cation transporter genes are associated with Crohn disease.  Nat. Genet. 36:471-5.

Pardossi-Piquard R, Petit A, Kawarai T, Sunyach C, Alves da Costa C, Vincent B, Ring S, D-Adamio L, Shen J, Muller U, St George-Hyslop P, and Checker F. 2005. Presenilin-dependent transcriptional control of the Abetadegrading enzyme neprilysin by intracellular domains of betaAPP and APLP.  Neuron 46:541-54.