MAINE MEDICAL CENTER
AVAILABLE TECHNOLOGIES
COPPER-DEPENDENT NON-TRADITIONAL
PRO-INFLAMMATORY CYTOKINE EXPORT AND METHODS
COMPOSITIONS,
METHODS AND KITS RELATING TO CTHRC1, A NOVEL MODULATOR OF COLLAGEN MATRIX
MODULATION OF MESENCHYMAL AND METASTIC CELL GROWTH
COPPER-DEPENDENT NON-TRADITIONAL PRO-INFLAMMATORY
CYTOKINE EXPORT AND METHODS
Inventor: Igor Prodovosky, Thomas Maciag, et. al.
Summary
of Invention: The inventors
have discovered that non-traditional export of certain pro-inflammatory
cytokines lacking a signal sequence from a cell can be inhibited by
copper chelation. Copper
chelation inhibits neointima formation, macrophage infiltration and associated
inflammation, cell proliferation, secretion of extracellular matrix,
intimal thickening, adventitial angiogenesis, restenosis, and vascular
vessel injury in general. This invention describes a unique way
of managing Interleukin-1 and FGF activity at the cellular level, which
leads to the opportunity for a variety of therapeutic benefit. In
vivo data has been generated and is available under a confidentiality
agreement.
Advantages: This
invention provides novel methods for preventing and treating various
vessel injury diseases
Patent
Status: Patent application, 8/24/01
For more information contact:
Todd Keiller
Technology Transfer
Maine Medical Center
508-497-2497
keillt@mmc.org
COMPOSITIONS,
METHODS AND KITS RELATING TO CTHRC1, A NOVEL MODULATOR OF COLLAGEN MATRIX
Inventor: Volkhard
Lindner
Summary of Invention: The
invention relates to the discovery of a novel nucleic acid encoding
a mammalian adventitia-inducible bone expressed molecule termed CTHRC1
(collagen triple helix repeat containing 1), previously referred to
as REMODELIN, REMODEL and/or adventitia induced bone expressed molecule
(AIBE), and the proteins encoded thereby. Data has been generated
that demonstrates that CTHRC1 is a modulator of collagen matrices as
well as playing a role in arterial restenosis mediated by or associated
with adventitial fibrosis. CTHRC1 also plays a role in bone and
cartilage formation. Identification of CTHRC1 has important implications
in the development of therapeutics and diagnostics for, among other things,
adventitial fibrosis, arterial restenosis, negative remodeling, restenosis
due to wound healing, and anti-cancer therapy.
More specifically, nucleic acids encoding CTHRC1 have been isolated
in both rat and human, and have no significant homology to any known
cDNA sequence.
The data
disclosed demonstrate that expression of CTHRC1 is induced by vessel
injury in mammals. That is, CTHRC1 was expressed in balloon-injured
rat carotid arteries but not in normal, uninjured vessels. Furthermore,
CTHRC1 was expressed selectively in the adventitia of the injured vessel,
and was not expressed in the neointima or in the adventitia of normal
vessels. Moreover, CTHRC1 expression was induced by TGF-β. This
is important since proliferative events occurring in the adventitia contribute
to vascular remodeling and restenosis in response to vascular injury
and recent data demonstrate that TGF-b is a factor in this adventitial
remodeling process. Thus, these data further indicate that CTHRC1
plays a role in cell proliferation and/or migration associated with vessel
injury and restenosis due to negative remodeling.
In sum,
the data disclosed herein demonstrate that CTHRC1 plays a role in cell
proliferation and/or migration and is involved in cellular signaling. Furthermore,
the data demonstrate that CTHRC1 likely plays a role in adventitial fibrosis,
negative remodeling and arterial restenosis, mediated by, among other
things, smooth muscle cell proliferation. An in vitro model
has been developed for the study of the function and role(s) of CTHRC1
in arterial remodeling, adventitial fibrosis, and restenosis in vessels,
as well as potential therapeutics and diagnostics for treatment of diseases,
disorders or conditions associated with adventitial fibrosis, arterial
restenosis, bone density and bone growth.
Patent
Status: Several patents pending
Issued
Patent # 6,630,325, October 7, 2003
For more information contact:
Todd Keiller
Technology Transfer
Maine Medical Center
508-497-2497
keillt@mmc.org
MODULATION OF MESENCHYMAL AND METASTIC CELL GROWTH
Inventor: Douglas
Spicer
Summary of Invention: Twist is a basic-Helix-Loop-Helix (bHLH) transcription factor that plays
both positive and negative roles in the regulation of early morphogenesis
and differentiation of mesenchymal tissues. Small changes in Twist expression
have profound phenotypic effects as exemplified by TWIST haploinsufficiency
resulting in craniofacial and limb abnormalities. In our efforts to better
characterize the molecular basis of Twist function we have found that
the activity of Twist depends on its dimer partner. Unlike most other
bHLH proteins, we find that Twist can form functional homodimers (T/T)
as well as heterodimers with ubiquitously expressed bHLH E proteins (T/E).
We find the Twist dimers have distinct activities, regulating the expression
of different sets of genes and have opposing effects on cell proliferation
and migration. We have two animal models indicating that the dimers have
different affects on cell behavior in vivo as well. (1) Twist haploinsufficiency
in both humans and mice leads to premature fusion of the cranial sutures.
We have found that this is due to an increase in T/T formation and we
can prevent suture fusion by promoting T/E formation. (2) Increased Twist
expression has been found in several different types of tumors and it
has been implicated as being important for metastasis to occur. In a
breast tumor model we have found that T/T dimers promote tumor cell invasion
into host tissues and increased tumor vasculature while T/E dimers inhibit
both of these processes. Therefore, regulating Twist dimer formation
may be a good therapeutic target to try and modulate cell behavior in
a number of different circumstances.
Advantages
over existing technology: The
only published method to alter Twist function has been antisense RNA
and siRNA. While these methods were effective the delivery of these
molecules is difficult. Targeting Twist dimerization may be performed
by small molecules that bind to Twist or E proteins to inhibit dimerization
and would be easily delivered.
Patent Status: patent pending
References:
Connerney, J., Y. Leshem, V. Andreeva, C. Muentener, M. Mercado,
and D.B. Spicer. (2006) Twist
dimer selection regulates cranial suture patterning and fusion. Dev.
Dyn. 235: 1345-1357.
For
more information contact:
Todd Keiller
Technology Transfer
Maine Medical Center
508-497-2497
keillt@mmc.org
