Enzo Biochem, Inc.

University of Connecticut

St. Jude's Childrens Hospital

Enzo Therapeutics, Inc.

Yazhou Zhang

Xiaofeng Li

Elazar S Rabbani

James J Donegan

Dakai Liu

Richard Jin

Wei Cheng

Riddhi Bhattacharyya

Dean L Engelhardt

Dianqing Wu

Vincenzo Enea

Peng Liu

Guangrong Zhang

Jie Zhang

Jufang Shan

Elazar Rabbani

Yuanxing Liang

The present invention relates to the field of therapeutic methods, compositions and uses thereof, that affect, directly or indirectly, the behavior of LRP receptors. These compositions and methods result in the treatment of inflammatory, immunological and metabolic conditions. More particularly, the methods and compositions of the invention are directed to the identification of small molecules, drugs and/or pharmacological agents that affect the Wnt pathway by affecting normal complex formation among various signaling receptors, the LRP5 and LRP6 receptor, and related ligands.

Method for treating crohn'S disease or ulcerative colitis by administering a compound which binds LDL-receptor-related protein (LRP) ligand binding domain

Method for treating inflammation by administering a compound which binds LDL-receptor-related protein (LRP) ligand binding domain

The mechanism by which the high bone mass (HBM) mutation (G171V) of the Wnt coreceptor LRP5 regulates the canonical Wnt signaling was investigated. The mutation was previously shown to reduce Dkk protein-1-mediated antagonism, suggesting that the first YWTD repeat domain where G171 is located may be responsible for Dkk protein-mediated antagonism. However, we found that the third YWTD repeat, but not the first repeat domain, is required for DKK1-mediated antagonism. Instead, we found that the G171V mutation disrupted the interaction of LRP5 with Mesd, a chaperon protein for LRP5/6 that is required for the coreceptors' transport to cell surfaces, resulting in less LRP5 molecules on the cell surface. Although the reduction in the level of cell surface LRP5 molecules led to a reduction in Wnt signaling in a paracrine paradigm, the mutation did not appear to affect the activity of coexpressed Wnt in an autocrine paradigm. Together with the observation that osteoblast cells produce autocrine canonical Wnt, Wnt7b, and that osteocytes produce paracrine Dkk1, we believe that the G171V mutation may cause an increase in Wnt activity in osteoblasts by reducing the number of targets for paracrine Dkk1 to antagonize without affecting the activity of autocrine Wnt.

Compositions and methods for bone formation and remodeling

Growing community of inventors

South Setauket, NY, United States of America

Yazhou Zhang