Current Search: notch (x)
-
-
Title
-
TRANSPLANTATION OF PLURIPOTENT STEM CELLS CONFERS CARDIAC PROTECTION IN DOX-INDUCED HEART FAILURE THROUGH NOTCH-1 PATHWAY.
-
Creator
-
Merino-Chavez, Hilda, Singla, Dinender, Zervos, Antonis, Naser, Saleh, University of Central Florida
-
Abstract / Description
-
Doxorubicin (DOX) is the antineoplastic drug of preference used to treat a wide variety of malignancies, with high survival rates among treated patients. However, the benefits of this drug have become less appealing due to the side effects that occur such as DOX-induced cardiomyopathy (DIC) and an increased risk of myocardial infarction (MI). Therefore, there is an urgent need to explore the therapeutic options to treat DIC. In this context, adult stem cells have been used as a source to...
Show moreDoxorubicin (DOX) is the antineoplastic drug of preference used to treat a wide variety of malignancies, with high survival rates among treated patients. However, the benefits of this drug have become less appealing due to the side effects that occur such as DOX-induced cardiomyopathy (DIC) and an increased risk of myocardial infarction (MI). Therefore, there is an urgent need to explore the therapeutic options to treat DIC. In this context, adult stem cells have been used as a source to reduce cardiomyocyte apoptosis in DIC; however, the effects of transplanted embryonic stem (ES) cells and induced pluripotent stem (iPS) cells in DIC post MI are unknown. As a result, we wanted to understand how transplanted ES and iPS cells and the factors released by them inhibit apoptosis and improve cardiac function in DIC post MI. C57BL/6 mice were divided into five groups: Sham, DOX-MI, DOX-MI+cell culture (CC) media, DOX-MI+ES cells, and DOX-MI+iPS cells. Mice were treated with DOX (12 mg/kg, cumulative dose) followed by left coronary artery ligation to induce MI. ES or iPS cells (5 x 104) were delivered into the peri-infarct region. At day 14 post-MI, echocardiography was performed, mice sacrificed, and hearts harvested for further analyses. To investigate if protective effects are provided by factors released from ES and iPS cells in DIC, we performed in vitro studies using condition media (CM) obtained from ES or iPS cells to treat DOX-induced cardiotoxicity in H9c2 cells. Our data reveal that apoptosis was significantly inhibited in the ES and iPS cell transplanted hearts as well as ESCM and iPSCM treated cells compared with the untreated controls. Furthermore, a significant increase in levels of Notch-1, Hes1, and pAkt survival protein were observed. Decreased levels of PTEN, a negative regulator of Akt pathway, along with improved heart function were also observed in the stem cell transplanted groups. In conclusion, our data show that transplantation of ES and iPS cells blunt DOX-induced apoptosis in vivo, which is associated with improved cardiac function. Moreover, decreased apoptosis in both in vitro and in vivo models is mediated by the Notch pathway.
Show less
-
Date Issued
-
2012
-
Identifier
-
CFE0004577, ucf:49213
-
Format
-
Document (PDF)
-
PURL
-
http://purl.flvc.org/ucf/fd/CFE0004577
-
-
Title
-
THE ENDOCYTIC PROTEIN NUMB REGULATES APP METABOLISM AND NOTCH SIGNALING: IMPLICATIONS FOR ALZHEIMER'S DISEASE.
-
Creator
-
Kyriazis, George, Chan, Sic, University of Central Florida
-
Abstract / Description
-
Increased production of amyloid beta (A-beta) peptide, via altered proteolytic cleavage of amyloid protein precursor (APP), and abnormalities in neuronal calcium homeostasis play central roles in the pathogenesis of Alzheimer's disease (AD). Notch1, a membrane receptor that controls cell fate decisions during development of the nervous system, has been linked to AD because it is a substrate for the gamma-secretase protein complex in which mutations cause early-onset inherited AD. Numb is...
Show moreIncreased production of amyloid beta (A-beta) peptide, via altered proteolytic cleavage of amyloid protein precursor (APP), and abnormalities in neuronal calcium homeostasis play central roles in the pathogenesis of Alzheimer's disease (AD). Notch1, a membrane receptor that controls cell fate decisions during development of the nervous system, has been linked to AD because it is a substrate for the gamma-secretase protein complex in which mutations cause early-onset inherited AD. Numb is an evolutionarily conserved endocytic adapter involved in the internalization of transmembrane receptors. Mammals produce four Numb isoforms that differ in two functional domains, a phosphotyrosine-binding domain (PTB) and a proline-rich region (PRR). Recent studies showed that the PTB domain of Numb interacts with the cytoplasmic tails of APP and Notch but the functional relevance of these interactions with respect to AD pathogenesis is not clear. In the current studies, we proposed to investigate the biological consequences of the interaction of the Numb proteins with APP and Notch in neural cells stably overexpressing each of the four human Numb proteins. In the first part of our studies, we found that expression of the Numb isoforms lacking the insert in the PTB (SPTB-Numb) caused the abnormal accumulation of cellular APP in the early endosomes, and increased the levels of C-terminal APP fragments and A-beta. By contrast, expression of the Numb isoforms with the insert in PTB (LPTB-Numb) leads to the depletion of cellular APP and coincides with significantly lower production of APP derivatives and A-beta. The contrasting effects of the Numb isoforms on APP metabolism were not attributed to differences in the expression of APP nor the activities of the various APP-processing secretases. In the second part of our studies, we found that expression of SPTB-Numb protein enhances neuronal vulnerability to serum deprivation-induced cell death by a mechanism involving the dysregulation of cellular calcium homeostasis. Neural cells expressing SPTB-Numb exhibited enhanced Notch activity, which markedly upregulated the expression of transient receptor potential canonical 6 (TRPC6) channels enhancing calcium entry in response to store depletion. We also found that serum deprivation increased TRPC6 expression, mediating the serum deprivation-induced death in neural cells. Interestingly, expression of LPTB-Numb protein suppressed serum deprivation-induced activation of Notch and the subsequent upregulation of TRPC6 and cell death. Finally, we showed that the Numb proteins differentially impact Notch activation by altering the endocytic trafficking and processing of Notch. Taken together, these studies demonstrate that aberrant expression of the Numb proteins may influence APP metabolism and Notch-mediated cellular responses to injury by altering their endocytic trafficking and processing.
Show less
-
Date Issued
-
2008
-
Identifier
-
CFE0002233, ucf:47917
-
Format
-
Document (PDF)
-
PURL
-
http://purl.flvc.org/ucf/fd/CFE0002233
-
-
Title
-
Thermomechanical Fatigue Life Prediction of Notched 304 Stainless Steel.
-
Creator
-
Karl, Justin, Gordon, Ali, Bai, Yuanli, Raghavan, Seetha, Nicholson, David, University of Central Florida
-
Abstract / Description
-
The behavior of materials as they are subjected to combined thermal and mechanical fatigue loads is an area of research that carries great significance in a number of engineering applications. Power generation, petrochemical, and aerospace industries operate machinery with expensive components that undergo repeated applications of force while simultaneously being exposed to variable temperature working fluids. A case of considerable importance is found in steam turbines, which subject blades...
Show moreThe behavior of materials as they are subjected to combined thermal and mechanical fatigue loads is an area of research that carries great significance in a number of engineering applications. Power generation, petrochemical, and aerospace industries operate machinery with expensive components that undergo repeated applications of force while simultaneously being exposed to variable temperature working fluids. A case of considerable importance is found in steam turbines, which subject blades to cyclic loads from rotation as well as the passing of heated gases. The complex strain and temperature histories from this type of operation, combined with the geometric profile of the blades, make accurate prediction of service life for such components challenging. Development of a deterministic life prediction model backed by physical data would allow design and operation of turbines with higher efficiency and greater regard for reliability. The majority of thermomechanical fatigue (TMF) life prediction modeling research attempts to correlate basic material property data with simplistic strain and thermal histories. With the exception of very limited cases, these types of efforts have been insufficient and imprecise in their capabilities. Early researchers did not account for the multiple damage mechanisms that operate and interact within a material during TMF loads, and did not adequately address the extent of the relationship between smooth and notched parts. More recent research that adequately recognizes the multivariate nature of TMF develops models that handle life reduction through summation of constitutive damage terms. It is feasible that a modification to the damage-based approach can sufficiently include cases that involve complex geometry. The focus of this research is to construct an experimentally-backed extension of the damage-based approach that improves handling of geometric discontinuities. Smooth and notched specimens of Type 304 stainless steel were subjected to several types of idealized fatigue conditions to assemble a clear picture of the types of damage occurring in a steam turbine and similarly-loaded mechanical systems. These results were compared with a number of idealized TMF experiments, and supplemented by numerical simulation and microscopic observation. A non-uniform damage-summation constitutive model was developed primarily based on physical observations. An additional simplistic model was developed based on phenomenological effect. Findings from this study will be applicable to life prediction efforts in other similar material and load cases.
Show less
-
Date Issued
-
2013
-
Identifier
-
CFE0004870, ucf:49666
-
Format
-
Document (PDF)
-
PURL
-
http://purl.flvc.org/ucf/fd/CFE0004870
-
-
Title
-
REELIN SIGNALING PROMOTES RADIAL GLIA MATURATION AND NEUROGENESIS.
-
Creator
-
Keilani, Serene, Sugaya, Kiminobu, University of Central Florida
-
Abstract / Description
-
The end of neurogenesis in the human brain is marked by the transformation of the neural progenitors, the radial glial cells, into astrocytes. This event coincides with the reduction of Reelin expression, a glycoprotein that regulates neuronal migration in the cerebral cortex and cerebellum. A recent study showed that the dentate gyrus of the adult reeler mice, with homozygous mutation in the RELIN gene, have reduced neurogenesis relative to the wild type. Based on the above findings, our...
Show moreThe end of neurogenesis in the human brain is marked by the transformation of the neural progenitors, the radial glial cells, into astrocytes. This event coincides with the reduction of Reelin expression, a glycoprotein that regulates neuronal migration in the cerebral cortex and cerebellum. A recent study showed that the dentate gyrus of the adult reeler mice, with homozygous mutation in the RELIN gene, have reduced neurogenesis relative to the wild type. Based on the above findings, our first hypothesis states that Reelin expression is important for the formation of radial glia and the generation of neurons from the neural progenitors. In order to investigate the role of Reelin in the process of cortical neurogenesis during development, we used human neural progenitor cells (hNPCs) that were isolated from a fetal cortex. These cells do not express Reelin. In this study, we show that Reelin addition to these hNPCs in vitro induced the formation of radial glia and increased neurogenesis significantly. Next, we investigated the mechanism by which Reelin increases the formation of radial glia and the generation of neurons. The formation of radial glia is under the control of two pathways, these are the Reelin and the Notch-1 signaling pathways. Since the level of Notch-1 activation determines if a cell would become a radial glia or an astrocyte, and since the absence of Reelin allows the transformation of a radial glia into astrocyte, we hypothesized that Reelin induces the formation of radial glia via activating Notch-1 signaling. To test this hypothesis, we investigated the effect of Reelin addition on Notch-1 activation in hNPCs. We found that Reelin addition in vitro activated Notch-1 signaling by increasing the level of Notch-1 intracellular domain (NICD). On the other hand, reducing NICD release, by inhibiting gamma-secretase activity, inhibited the Reelin-induced radial glia, confirming that Reelin's effect on the formation of radial glia is dependent on Notch-1 activation. Furthermore, we found that the Reelin-induced tyrosine phosphorylation of Disabled-1 (Dab-1), an adaptor protein downstream of Reelin, and the subsequent activation of Src family kinases, are essential steps for Notch-1 activation by Reelin. Finally, we found that Reelin addition increased the binding of Dab-1, recently identified as a nucleoshuttling protein, to NICD and enhanced NICD translocation to the nucleus. This resulted in the induction of BLBP expression and the subsequent formation of radial glia. Taken together, these data show that Reelin signaling, mediated by Dab-1 and Src kinase, activates Notch-1 signaling in hNPCs resulting in the induction of BLBP expression, the formation of radial glia and the generation of neurons. This work is novel because it provides that first evidence that Reelin expression is an important signal for the neuronal differentiation of the hNPCs. It also shows the crosstalk between Reelin and Notch-1 signaling, two major pathways in development and cell fate determination. The work is significant because it improves our understanding of the role of Reelin signaling in cell fate determination, differentiation and neurogenesis for the future manipulation of these processes to restore adult brain functions after brain injury or in neurodegenerative diseases.
Show less
-
Date Issued
-
2009
-
Identifier
-
CFE0002574, ucf:48258
-
Format
-
Document (PDF)
-
PURL
-
http://purl.flvc.org/ucf/fd/CFE0002574
-
-
Title
-
A SIMPLIFIED APPROACH TO THERMOMECHANICAL FATIGUE AND APPLICATION TO V-SHAPED NOTCHES.
-
Creator
-
Bouchenot, Thomas, Gordon, Ali, University of Central Florida
-
Abstract / Description
-
A vast array of high value parts in land- and air-based turbomachinery are subjected to non-isothermal cycling in the presence of mechanical loading. Crack initiation, growth and eventual failure more significantly reduce life in these components compared to isothermal conditions. More accurate simulation of the stress and strain evolution at critical locations of components, as well as test specimens, can lead to a more accurate prediction of remaining life to a structural integrity...
Show moreA vast array of high value parts in land- and air-based turbomachinery are subjected to non-isothermal cycling in the presence of mechanical loading. Crack initiation, growth and eventual failure more significantly reduce life in these components compared to isothermal conditions. More accurate simulation of the stress and strain evolution at critical locations of components, as well as test specimens, can lead to a more accurate prediction of remaining life to a structural integrity specialists. The focus of this thesis is to characterize the effects of thermomechanical fatigue (TMF) on generic turbomachinery alloy. An expression that can be used to estimate the maximum and minimum stress under a variety of loading conditions is formulated. Analytical expressions developed here are modifications of classic mechanics of materials methods (e.g. Neuber's Rule and Ramberg-Osgood). The novel models are developed from a collection of data based on parametric finite element analysis to encompass the complex load history present in turbine service conditions. Relevance of the observations and formulated solutions are also explored for the case of a tensile specimen containing a v-shaped notch. Accurate estimations of non-isothermal fatigue presented here endeavor to improve component lifing and decrease maintenance costs.
Show less
-
Date Issued
-
2013
-
Identifier
-
CFH0004480, ucf:45073
-
Format
-
Document (PDF)
-
PURL
-
http://purl.flvc.org/ucf/fd/CFH0004480