Identification and Function of nuDMP1 in Odontoblast Differentiation

Summary

Principal Investigator: Yongbo Lu
Abstract: DESCRIPTION (provided by applicant): The loss of dentin matrix protein 1 (DMP1) function in humans and mice results in autosomal recessive hypophosphatemic rickets (ARHR), characterized by hypomineralization in dentin and bone, hypophosphatemia and the elevation of circulating fibroblast growth factor 23 (FGF23) levels. The dental and skeletal defects of Dmp1-deficient subjects have been attributed to the combined effects of the intrinsic differentiation defects of Dmp1-null odontoblasts and osteoblasts/osteocytes (local effect) and hypophosphatemia (systemic effect). However, the way in which the loss of DMP1 function causes the differentiation defects of odontoblasts and osteoblasts/osteocytes remains largely unknown. The goal of this application is to identify a nuclear isoform(s) of DMP1 (referred to as "nuDMP1") and to study its function in odontoblast differentiation. We hypothesize that nuDMP1 is translated from alternative downstream in-frame AUG start codon(s) and controls odontoblast differentiation by regulating Dspp expression. This hypothesis is based on our recent in vitro and in vivo findings, which include: 1) nuclear DMP1 is observed in cells transfected with a construct expressing full-length DMP1 with the endoplasmic reticulum (ER)-entry signal peptide sequence;2) a construct expressing full-length DMP1 without the ER-entry signal peptide sequence produces two proteins, a full-length DMP1 and a putative nuDMP1;3) a construct producing the putative nuDMP1 is more potent at stimulating Dspp promoter activity than those producing full-length DMP1 with or without the ER-entry signal peptide;and 4) the transgenic overexpression of DSPP driven by a 3.6 kb Col1a1 promoter rescues the dental defects but not the other manifestations of Dmp1-null mice. To test our central hypothesis, three specific aims are proposed. Aim 1 will determine the mechanisms by which the nuDMP1 is generated and subsequently translocated into the nuclei. Aim 2 will investigate the function of the nuDMP1 in odontoblast differentiation in vivo by generating and characterizing the 3.6 kb Col1a1-nuDMP1 transgenic mice. Aim 3 will determine how Dspp expression is activated through nuDMP1 and if the failure of this process is solely responsible for the tooth phenotype in Dmp1-null mice. Successful completion of this novel proposal will provide unique insights into how DMP1 regulates cell differentiation via the nuDMP1, which is independent of its function in regulating matrix mineralization. The identification of this novel nuDMP1 and its function will not only help elucidate the molecular mechanisms through which DMP1 controls the formation of tooth and bone but will also provide a scientific basis for developing therapies for treatment of hypophosphatemic rickets.
Funding Period: 2013-04-01 - 2017-03-31
more information: NIH RePORT

Research Grants

Detail Information

Research Grants30

  1. HORMONAL CONTROL OF CALCIUM METABOLISM
    John T Potts; Fiscal Year: 2013
    ....
  2. The Mechanistic Control of Bone Matrix Material Properties by TGF-beta and Runx2
    TAMARA N ALLISTON; Fiscal Year: 2013
    ..This will lead to a closer examination of their regulation in healthy bone or their misregulation during disease processes. ..
  3. Sp7 Mediated Control of Runx2 Function for Osteoblast Differentiation
    Amjad Javed; Fiscal Year: 2013
    ..Knowledge obtained from this study will provide molecular insights into components of bone regulatory complex that can be targeted for innovative therapy to improve cartilage and bone formation and repair. ..
  4. The Roles of FAM20C (DMP4) in Odontogenesis and Osteogenesis
    Chunlin Qin; Fiscal Year: 2013
    ....
  5. Role of FoxOs in Skeletal Homeostasis
    MARIA JOSE ALMEIDA; Fiscal Year: 2013
    ..Increased understanding of the mechanisms that control bone formation will provide important information for the development of therapies to maintain or increase bone mass and strength, thereby reducing the risk of osteoporotic fractures ..
  6. FGF-23 REGULATION OF PHOSPHATE HOMEOSTASIS
    Kenneth E White; Fiscal Year: 2013
    ..We expect these studies to provide novel, translational insight into rare and common syndromes of altered FGF23 expression and into the basic biology of phosphate homeostasis. ..
  7. Control of Bone Formation in Craniometaphyseal Dysplasia
    ERNST J REICHENBERGER; Fiscal Year: 2013
    ..We also expect a broad impact on the field of bone remodeling as the mutation in this animal model affects some key mechanisms for bone mineralization and regulation of bone cells. ..
  8. Mitochondrial Dysfunction in Neurodegeneration of Aging
    Gary E Gibson; Fiscal Year: 2013
    ..Successful completion of the goals of these projects can be expected to provide new insights into neurodegenerative processes and contribute to novel approaches to ameliorating age-related neurodegenerations. ..
  9. Cellular Senescence and Aging
    James L Kirkland; Fiscal Year: 2013
    ..Our approach will provide timely, innovative, and clinically relevant interventional results based on addressing the fundamental question of the role of cellular senescence that has remained unanswered for many years. ..
  10. The Biology of Prostate Cancer Skeletal Metastases
    EVAN TODD KELLER; Fiscal Year: 2013
    ..This combination of investigators, projects and cores result in a highly synergistic Program that will continue to provide cutting-edge research on PCa bone metastases. ..
  11. DMP1 and DSPP in Osteogenesis and Dentinogenesis
    Albert K Yamoah; Fiscal Year: 2013
    ..Award of the F30 fellowship is necessary for me to fulfill the specific aims and to get training on my way towards becoming an independent dentist scientist. ..