This application proposes innovative studies of the parathyroid gland in the context of chronic kidney disease (CKD). CKD is a major, world-wide health concern and new data with clinical relevance are critical to developing new methods for treatment of the serious complications of this disease that involve the parathyroid gland. CKD is a complex disease that begins with degradation in kidney function and is characterized by a multitude of systemic problems as it progresses to its end stages. The most severe systemic problems are related to the mineral and hormonal imbalances that instigate secondary hyperparathyroidism accompanied by parathyroid gland hyperplasia, which is the most significant cause of morbidity and mortality in CKD patients. The mechanisms underlying the breakdown in regulatory controls that lead to hyperplasia are only partially understood. We propose two research aims that seek to expand the understanding of this serious medical issue.
Our first aim i s to develop a more comprehensive understanding of the role for Klotho that is expressed in the parathyroids. Klotho is expressed in the parathyroid gland and has been shown to regulate PTH production by acting as co-factor for FGF23, a key regulator of phosphate homeostasis. We have novel preliminary data that show for the first time that Klotho may have an additional role of modulating the response to changes in serum calcium.
Our second aim i s to pursue data we generated from the first ever microarray analysis of mouse parathyroid glands. Our analysis has discovered the expression of some genes in hyperplasic glands that have not been reported or studied previously. We have selected one gene, Fgfr2, as a high interest target for further study to determine its role in the induction and progression of hyperplasia. We will use our innovative technique for isolating total mRNA from mouse parathyroid glands in combination with our transgenic mouse models to study the role and mechanisms of this gene in the development and maintenance of hyperplasia and to identify key partner genes in this process. The data we expect to generate is of high clinical relevance given the serious medical and economic effects of CKD.

Public Health Relevance

The parathyroid gland produces parathyroid hormone in response to low serum calcium to maintain mineral homeostasis, but due to its small size and the lack of any in vitro models only limited studies of its function are possible. Patients with chronic kidney failure develop secondary hyperparathyroidism which is associated with renal osteodystrophy, extra-skeletal calcification, bone mineralization problems and cardiovascular disease and is thus a major factor in morbidity in CKD patients. Our proposed research uses novel techniques to investigate the causes for the development of parathyroid gland hyperplasia and SHPT.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01DK097105-03
Application #
8681436
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Malozowski, Saul N
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Harvard Medical School
Department
Dentistry
Type
Schools of Dentistry/Oral Hygn
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02115
Lanske, Beate; Razzaque, Mohammed S (2014) Molecular interactions of FGF23 and PTH in phosphate regulation. Kidney Int 86:1072-4
Ma, Yue; Samaraweera, Manoharee; Cooke-Hubley, Sandra et al. (2014) Neither absence nor excess of FGF23 disturbs murine fetal-placental phosphorus homeostasis or prenatal skeletal development and mineralization. Endocrinology 155:1596-605
Lysaght, Andrew C; Yuan, Quan; Fan, Yi et al. (2014) FGF23 deficiency leads to mixed hearing loss and middle ear malformation in mice. PLoS One 9:e107681
Lanske, Beate; Densmore, Michael J; Erben, Reinhold G (2014) Vitamin D endocrine system and osteocytes. Bonekey Rep 3:494