MVNP, p62P392L and IL-6 in the Pathogenesis of PD

Project: Research project

Description

SPACE
PROVIDED.
The role of the measles virus nucleocapsid gene (MVNP) and p62p392L in PD are just beginning to be
clarified. However, how they may interact to cause PD and the cellular and molecular mechanisms involved
are still unclear. It is our hypothesis that both an environmental factor (MVNP) and a genetic factor (p62P392L)
contribute to the development of PD, and that many of the effects of MVNP are mediated through its
induction of high levels of IL-6 in cells of the OCL lineage. Project 2 will examine the cellular and in vivo
effects of co-expression of MVNP and p62p392L, and the mechanisms involved in the development of PD.
Studies in Project 1, which are closely linked to Project 2, will examine the molecular mechanisms involved
n the effects of MVNP and p62PS92L that result in formation of PD OCL and increased IL-6 production. To
test this hypothesis, we will: 1. Determine if co-expression of MVNP and p62P394L induce Paget's disease in
mice. We will mate mice in which the MVNP gene is targeted to the OCL lineage (TRAP-MVNP mice) with
p62P394L Kl (p62KI) mice. We will determine if OCLs with the characteristics of PD OCLs form in vitro, and
assess the bone phenotype of these mice in terms of OCL and osteoblast activity, OCL morphology,
histomorphometry and the development and extent of pagetic bone lesions. The molecular basis for the
changes in OCL and osteoblast activity that occur upon co-expression of MVNP and p62p394L in mice will be
characterized in Projects 1 and 3 respectively. 2. Determine if increased IL-6 expression induced by MVNP
in OCL is responsible for the development of pagetic OCLs and bone lesions in TRAP-MVNP mice. TRAP-
MVNP will be mated with IL-6'A mice to generate TRAP-MVNP/IL-B"'' mice. The OCL and osteoblast
phenotype of these mice, as well as their capacity to develop focal bone lesions characteristic of PD, will be
compared to WT, TRAP-MVNP and IL-6J" mice. As part of these experiments, we will determine if blocking
IL-6 activity with a neutralizing antibody to IL-6 inhibits the development of pagetic OCLs in marrow cultures
from patients with PD. 3. Test the hypothesis that increased expression of IL-6 and the presence of the
p62P394L mutation are sufficient to induce pagetic bone lesions and OCL in mice. We have previously shown
that the p62KI mice do not develop pagetic bone lesions, and that OCL from these mice are not hyper-
multinucleated or hyper-responsive to 1,25-(OH)2D3, and do not produce elevated levels of IL-6, features
characteristic of PD OCLs. Therefore, we will generate TRAP-IL-6 mice in which expression of IL-6 is
targeted to cells of the OCL lineage, and interbreed them to the p62KI mice. The TRAP-IL-6/p62KI mice wil
be characterized with regard to their bone phenotype and OCL and osteoblast activity in vitro and vivo, and
the effects of increased IL-6 expression and p62P392L mutation on NFicB and p38 MAPK signaling in OCLs
and stromal cells from these mice. As part of these experiments, we will treat normal human OCL precursors
transfected with p62P392L with varying concentrations of IL-6 to determine if they form OCLs that express a
complete pagetic phenotype.
StatusFinished
Effective start/end date9/15/084/30/19

Funding

  • National Institutes of Health: $380,305.00
  • National Institutes of Health: $171,520.00
  • National Institutes of Health: $610,272.00
  • National Institutes of Health: $369,495.00
  • National Institutes of Health: $349,723.00
  • National Institutes of Health: $345,005.00
  • National Institutes of Health: $144,762.00
  • National Institutes of Health: $393,822.00
  • National Institutes of Health: $336,592.00
  • National Institutes of Health: $331,179.00

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Interleukin-6
Nucleocapsid
Measles virus
Osteoclasts
Osteoblasts
Genes
Bone and Bones
Osteogenesis
Phenotype
Cell Lineage
measles virus nucleocapsid protein
Mutation
Bone Resorption
p38 Mitogen-Activated Protein Kinases

ASJC

  • Medicine(all)