MECHANISMS OF OSTEOLYTIC BONE DESTRUCTION

点击翻译按钮获取中文摘要

DESCRIPTION (Applicant's Description): The candidate is a graduate of the University of Puerto Rico School of Medicine and has completed an academic Fellowship in Hematology/Oncology at the University of Texas Health Science Center (UTHSC) in 1995 and plans to pursue a career in academic medicine and basic research. This award will be used to develop the candidate's research skills in cellular and molecular biology, and screening of novel osteoclast stimulatory factors in a highly supervised research setting. In collaboration with Dr. Roodman, the candidate has developed the first model of human myeloma bone disease in SCID mice and will use this model to investigate the mechanisms underlying myeloma bone disease. Osteoclast-mediated bone destruction is the major cause of morbidity in patients with myeloma, but its pathogenesis is unclear. The hypothesis that will be tested in the current proposal is that myeloma cells produce novel factors in vivo that stimulate osteoclast formation and bone resorption. The candidate has recently cloned a novel osteoclast stimulatory factor, expressed by myeloma cells, that will be sequenced and characterized as follows: (a) Using RT-PCR, expression of this factor will be confirmed in RNA from involved marrow samples from their in vivo model of myeloma bone disease and freshly isolated marrow from patients with multiple myeloma; (b) Using the techniques of in situ hybridization and immunocytochemistry, the cell types expressing this factor will be determined. In addition, the investigators will determine if this factor is expressed by normal CD19+ B cells by screening their previously prepared CD19+ B cell library; (c) The recombinant protein will be prepared; (d) The recombinant protein will be tested for its capacity to enhance osteoclast formation in human marrow cultures and bone resorption in bone organ cultures. The investigators will also continue their efforts to clone from their myeloma expression library osteoclast stimulatory factors from the other five positive expression pools that stimulate osteoclast formation in marrow cultures.