application) Mentored Research Scientist Development Award: The nominee, M. Chris Langub, Ph.D., proposes to develop as an independent investigator in the field of metabolic bone diseases at the Division of Nephrology, Bone and Mineral Metabolism. The focus is renal bone disease, a condition that affects virtually all patients with end stage renal failure (ESRD). It is known that parathyroid hormone (PTH), calcitriol, and interleukins act on bone of ESRD patients. New biomolecules, osteoclast differentiating factor (ODF) and receptor activator of NFkB (RANK), the receptor for ODF, and osteoprotegerin (OPG) have been implicated to directly affect bone resorption. ODF differentiates and activates cells of the osteoclast lineage by binding to RANK and OPG inhibits these pathways by preventing ODF from binding. The ratio of ODF:OPG has been shown in vitro to increase with PTH, calcitriol, and cytokine IL-11 administration. There is no information, however, about these new biomolecules in humans and their role in the wide spectrum of bone turnover in patients with ESRD. The hypotheses are 1) an imbalance between expression of these biomolecules in bone cells of ESRD patients is associated with the wide range of bone turnover in renal osteodystrophy, i.e., the ratio of OPG over ODF and/or RANK is decreased in patients with high bone turnover while the ratio of OPG over ODF and/or RANK is increased in patients with low bone turnover; and 2) serum levels of PTH, calcitriol, and cytokines IL-6 and IL-11 correlate with levels of expression of OPG over ODF and/or RANK and thus influence bone turnover.
The Specific Aim i s to establish the role of these novel biomolecules in the bone turnover abnormalities of patients with renal osteodystrophy. Specifically the objectives are 1) to localize and quantify expression of OPG, ODF, and RANK mRNAs and proteins in bone cells using in situ hybridization histochemistry, and immunohistochemistry; 2) to perform histomorphometric assessment of bone turnover, i.e., activation frequency and parameters of bone resorption and formation, and correlate data with objective 1; and 3) to determine by biochemical assays serum levels of PTH, calcitriol, cytokines IL-6, and IL-11 and correlate data with objectives 1 and 2. The long term goal is to understand the mechanisms of regulation of bone turnover in ESRD patients. This award will provide the trainee with solid foundation for a comprehensive training in renal bone disease and enhancement of molecular histomorphometric techniques. Altogether, the study and training will foster long term scientific productivity in the trainee's chosen field of bone pathology and biology.
| Alimov, Alexander P; Langub, M Chris; Malluche, Hartmut H et al. (2004) Contrasting mammalian parathyroid hormone (PTH) promoters: nuclear factor-Y binds to a deoxyribonucleic acid element unique to the human PTH promoter and acts as a transcriptional enhancer. Endocrinology 145:2713-20 |
| Yan, Feng-Xiang; Langub, M Chris; Ihnen, Mark A et al. (2003) CYP2D6, GST-M1 and GST-T1 enzymes: expression in parathyroid gland and association with the parathyroid hormone concentration during early renal replacement therapy. Br J Clin Pharmacol 56:68-77 |
| Alimov, Alexander P; Langub, M Chris; Malluche, Hartmut H et al. (2003) Sp3/Sp1 in the parathyroid gland: identification of an Sp1 deoxyribonucleic acid element in the parathyroid hormone promoter. Endocrinology 144:3138-47 |
