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Title: Positive modulator of bone morphogenic protein-2

Abstract

Compounds of the present invention of formula I and formula II are disclosed in the specification and wherein the compounds are modulators of Bone Morphogenic Protein activity. Compounds are synthetic peptides having a non-growth factor heparin binding region, a linker, and sequences that bind specifically to a receptor for Bone Morphogenic Protein. Uses of compounds of the present invention in the treatment of bone lesions, degenerative joint disease and to enhance bone formation are disclosed.

Inventors:
; ; ;
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1361549
Patent Number(s):
9,670,258
Application Number:
15/240,977
Assignee:
Brookhaven Science Associates, LLC LBNL
DOE Contract Number:
ACO2-98CH1086
Resource Type:
Patent
Resource Relation:
Patent File Date: 2016 Aug 18
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES

Citation Formats

Zamora, Paul O., Pena, Louis A., Lin, Xinhua, and Kazuyuki, Takahashi. Positive modulator of bone morphogenic protein-2. United States: N. p., 2017. Web.
Zamora, Paul O., Pena, Louis A., Lin, Xinhua, & Kazuyuki, Takahashi. Positive modulator of bone morphogenic protein-2. United States.
Zamora, Paul O., Pena, Louis A., Lin, Xinhua, and Kazuyuki, Takahashi. 2017. "Positive modulator of bone morphogenic protein-2". United States. doi:. https://www.osti.gov/servlets/purl/1361549.
@article{osti_1361549,
title = {Positive modulator of bone morphogenic protein-2},
author = {Zamora, Paul O. and Pena, Louis A. and Lin, Xinhua and Kazuyuki, Takahashi},
abstractNote = {Compounds of the present invention of formula I and formula II are disclosed in the specification and wherein the compounds are modulators of Bone Morphogenic Protein activity. Compounds are synthetic peptides having a non-growth factor heparin binding region, a linker, and sequences that bind specifically to a receptor for Bone Morphogenic Protein. Uses of compounds of the present invention in the treatment of bone lesions, degenerative joint disease and to enhance bone formation are disclosed.},
doi = {},
journal = {},
number = ,
volume = ,
place = {United States},
year = 2017,
month = 6
}

Patent:

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  • Compounds of the present invention of formula I and formula II are disclosed in the specification and wherein the compounds are modulators of Bone Morphogenic Protein activity. Compounds are synthetic peptides having a non-growth factor heparin binding region, a linker, and sequences that bind specifically to a receptor for Bone Morphogenic Protein. Uses of compounds of the present invention in the treatment of bone lesions, degenerative joint disease and to enhance bone formation are disclosed.
  • Hepatopulmonary syndrome (HPS) is characterized by an arterial oxygenation defect induced by intrapulmonary vasodilation (IPVD) that increases morbidity and mortality. In our previous study, it was determined that both the proliferation and the myogenic differentiation of pulmonary microvascular endothelial cells (PMVECs) play a key role in the development of IPVD. However, the molecular mechanism underlying the relationship between IPVD and the myogenic differentiation of PMVECs remains unknown. Additionally, it has been shown that bone morphogenic protein-2 (BMP2), via the control of protein expression, may regulate cell differentiation including cardiomyocyte differentiation, neuronal differentiation and odontoblastic differentiation. In this study, we observedmore » that common bile duct ligation (CBDL)-rat serum induced the upregulation of the expression of several myogenic proteins (SM-α-actin, calponin, SM-MHC) and enhanced the expression levels of BMP2 mRNA and protein in PMVECs. We also observed that both the expression levels of Smad1/5 and the activation of phosphorylated Smad1/5 were significantly elevated in PMVECs following exposure to CBDL-rat serum, which was accompanied by the down-regulation of Smurf1. The blockage of the BMP2/Smad signaling pathway with Noggin inhibited the myogenic differentiation of PMVECs, a process that was associated with relatively low expression levels of both SM-α-actin and calponin in the setting of CBDL-rat serum exposure, although SM-MHC expression was not affected. These findings suggested that the BMP2/Smad signaling pathway is involved in the myogenic differentiation of the PMVECs. In conclusion, our data highlight the pivotal role of BMP2 in the CBDL-rat serum-induced myogenic differentiation of PMVECs via the activation of both Smad1 and Smad5 and the down-regulation of Smurf1, which may represent a potential therapy for HPS-induced pulmonary vascular remodeling. - Highlights: • CBDL-rat serum promotes the myogenic differentiaton and expression of BMP2 in PMVECs. • CBDL-rat serum activates the BMP2/smad signaling pathway. • The downregulation of Smurf1 stimulates the accumulation of Smad1/5 in PMVECs. • Noggin reverses partially the myogenic differentiaton in PMVECs.« less
  • This patent describes a throttle valve actuator for an automatic transmission used with an internal combustion engine having an air-fuel intake manifold and having means on the air intake side thereof for supercharging the effective pressure therein; an actuator housing, a diaphragm in the housing cooperating with the housing to define a cavity on one side of the diaphragm, means for establishing pneumatic communication between the intake manifold and the cavity, spring means in the cavity for urging the diaphragm in one direction, the effective force on the diaphragm being the sum of the force of the spring and themore » pneumatic force of the pressure of the manifold; a seal ring situated in the housing and on the opposite side of the diaphragm and having a central opening of less area than the total area of the diaphragm, the central portion of the diaphragm being received over the opening; a valve stem adapted to establish a mechanical connection between the central diaphragm portion and a transmission throttle valve whereby the throttle valve is subjected to an actuating force that is the sum of the effective for of the pneumatic pressure on the diaphragm and the spring force; the opposite side of the diaphragm being adapted to establish a seal on the seal ring whereby the effective area over which a positive pressure in the manifold acts is equal to the area of the opening in the seal ring and wherein effective area of the diaphragm over which a negative pressure on the manifold acts is the total area of the diaphragm.« less
  • Highlights: Black-Right-Pointing-Pointer FGF modulates BMPs pathway in HMSCs by down-regulating BMP/BMPR expression. Black-Right-Pointing-Pointer This effect is mediated by ERK and JNK MAPKs pathways. Black-Right-Pointing-Pointer Crosstalk between FGF and BMPs must be taken into account in skeletal bioengineering. Black-Right-Pointing-Pointer It must also be considered in the use of recombinant BMPs in orthopedic and spine surgeries. -- Abstract: Understanding the interactions between growth factors and bone morphogenic proteins (BMPs) signaling remains a crucial issue to optimize the use of human mesenchymal stem cells (HMSCs) and BMPs in therapeutic perspectives and bone tissue engineering. BMPs are potent inducers of osteoblastic differentiation. They exertmore » their actions via BMP receptors (BMPR), including BMPR1A, BMPR1B and BMPR2. Fibroblast growth factor 2 (FGF2) is expressed by cells of the osteoblastic lineage, increases their proliferation and is secreted during the healing process of fractures or in surgery bone sites. We hypothesized that FGF2 might influence HMSC osteoblastic differentiation by modulating expressions of BMPs and their receptors. BMP2, BMP4, BMPR1A and mainly BMPR1B expressions were up-regulated during this differentiation. FGF2 inhibited HMSCs osteoblastic differentiation and the up-regulation of BMPs and BMPR. This effect was prevented by inhibiting the ERK or JNK mitogen-activated protein kinases which are known to be activated by FGF2. These data provide a mechanism explaining the inhibitory effect of FGF2 on osteoblastic differentiation of HMSCs. These crosstalks between growth and osteogenic factors should be considered in the use of recombinant BMPs in therapeutic purpose of fracture repair or skeletal bioengineering.« less
  • This patent describes a multispeed automatic transmission system for vehicles having transmission gears which shift from low to high to low in response to the acceleration and deceleration of the vehicle wherein a vacuum modulator control is mounted in the vacuum line between the vacuum modulator and the intake manifold. The improvement described here is in the vacuum modulator control. The control is adapted for mounting at any desired location in the engine compartment comprising a cylinder, a piston slidably positioned in the cylinder. The cylinder has a front end face and a rear end face and a peripheral surface.more » A resilient means is in the cylinder for urging the piston toward one of the end faces and a stop means in the cylinder remote from the resilient means limits the amount of movement of the piston in the cylinder. A first port communicates with the interior of the cylinder through the peripheral surface, the first port communicating with the vacuum modulator, second and third ports communicating with the interior of the cylinder through the peripheral surface. The second and third ports communicate with the intake manifold whereby during deceleration air flows into the cylinder through the first port and exits from the cylinder through the second and third ports with the piston being urged against the resilient means and whereby during acceleration air flows into the cylinder through the second and third ports and exits from the first port with the piston being urged away from the resilient means.« less