Case Western Reserve University
Grant: $353,250 - National Institutes of Health - Jul. 17, 2009
No votes have been cast for this award yet
Join the conversation: Post a comment about this award
Award Description: 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) is the bioactive hormone of the vitamin D endocrine system. It functions via the vitamin D receptor (VDR) to impact bone by increasing intestinal calcium absorption and by directly affecting osteoblast/osteoclast activity. The overall goal of this research proposal is to examine direct transcriptional effects of 1,25(OH)2D3 and VDR in osteoblasts. Toward this goal, expression arrays identified several novel genes that are induced by 1,25(OH)2D3 in osteoblastic cells. This proposal focuses on one 1,25(OH)2D3-induced gene that impact osteoblast biology, namely Meningioma-1 or MN1. MN1 is a transcription factor that serves as a coactivator in nuclear receptor- mediated transcription. Deletion of the MN1 gene in mice markedly impairs intramembranous ossification leading to defects in cranial skeletal development. These data demonstrate an important biological role for MN1 in skeletal homeostasis. Our preliminary data show that MN1 is expressed in numerous osteoblastic cell lines and its expression is regulated by 1,25(OH)2D3 in osteoblastic cells in vitro and in vivo. Ectopic expression of MN1 in osteoblasts inhibits osteoblast proliferation and shRNA- mediated knock-down of MN1 expression reduces osteoblast differentiation markers in vitro. These studies are the first to address MN1 function in skeletal homeostasis. A major hypothesis tested in this proposal is that VDR and 1,25(OH)2D3 are potent regulators of MN1 gene expression and of other genes that are required to maintain normal skeletal homeostasis. We propose to examine the significance of the vitamin D endocrine system in skeletal homeostasis by focusing on the continued characterization of MN1 in osteoblast function. Specifically, we propose to: 1) determine the significance of MN1 in development and maintenance of the appendicular and axial skeletons, 2) determine the molecular mechanisms involved in the transcriptional regulation of the MN1 gene by 1,25(OH)2D3 in osteoblastic cells, 3) establish the functional significance of MN1 in 1,25(OH)2D3-activated transcription in osteoblastic cells, and 4) determine the role of MN1 in controlling osteoblast proliferation and differentiation. These studies will provide new insight into the direct actions of the vitamin D endocrine system in skeletal homeostasis and an improved understanding of key factors that are needed to maintain skeletal integrity. PUBLIC HEALTH RELEVANCE: The molecular details involved in vitamin D effects in bone and osteoblasts are largely unknown. Our working hypothesis states that vitamin D controls the expression of the MN1 coactivator protein and impacts osteoblast function. The main goal of this proposal is to define novel target genes for VDR-RXR heterodimers in osteoblasts.
Project Description: The overall goal of this research proposal is to examine direct transcriptional effects of 1,25(OH)2D3 and VDR in osteoblasts. This proposal focuses on one 1,25(OH)2D3-induced gene that impact osteoblast biology, namely Meningioma-1 or MN1. MN1 is a transcription factor that serves as a coactivator in nuclear receptor- mediated transcription. Deletion of the MN1 gene in mice markedly impairs intramembranous ossification leading to defects in cranial skeletal development. These data demonstrate an important biological role for MN1 in skeletal homeostasis. A major hypothesis tested in this proposal is that VDR and 1,25(OH)2D3 are potent regulators of MN1 gene expression and of other genes that are required to maintain normal skeletal homeostasis. We are examining the significance of the vitamin D endocrine system in skeletal homeostasis by focusing on the continued characterization of MN1 in osteoblast function. Specifically, we propose to: 1) determine the significance of MN1 in development and maintenance of the appendicular and axial skeletons and 2) determine the role of MN1 in controlling osteoblast proliferation and differentiation. These studies will provide new insight into the direct actions of the vitamin D endocrine system in skeletal homeostasis and an improved understanding of key factors that are needed to maintain skeletal integrity.
Jobs Summary: Research Assistant I - The objective of this position is to efficiently perform laboratory investigations and to provide technical and organization support necessary for the productive and smooth operation of a research laboratory. The objectives of the research projects in this laboratory are to understand the molecular, cellular and physiological basis of the vitamin D endocrine system and gene regulation in various skin and skeletal models. This work will provide the basis for a better understanding of the role of the vitamin D endocrine system in health and disease. The Research Assistant I will carry out experiments utilizing various molecular and cell biological approaches as well as studies using various mouse models. He/she will keep meticulous notes, and will work closely with the PI. The Research Assistant I will also participate in laboratory maintenance chores and in maintaining records for health and biosafety matters. This position is supported 100% by these ARRA funds. Assistant Professor - This a senior level position that is responsible for co-direction of all research activities in the Priciple Investigator's laboratory. It is broad in scope including designing and performing experiments, writing manuscripts and grants, interpeting all data, mentoring and training students and research assistants. It is an essential position for all operations currently underway this reserch laboratory. This position is supported at a level of 50% using these ARRA funds. (Total jobs reported: 2)
Project Status: Less Than 50% Completed
This award's data was last updated on Jul. 17, 2009. Help expand these official descriptions using the wiki below.
No comments have been added for this project.