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Habibi I.,New Jersey Institute of Technology | Abdi A.,New Jersey Institute of Technology | Emamian E.S.,Advanced Technologies for Novel Therapeutics
2011 IEEE Signal Processing in Medicine and Biology Symposium, SPMB 2011 | Year: 2011

In this paper a systems biology framework for generalized fault diagnosis in the caspase signaling network of biomolecules is studied. This novel method is capable of identifying critical molecules whose dysfunction can affect the network function detrimentally. The generalized vulnerabilities defined and computed in the paper quantify the role of molecules in a complex network. Impact of network input activities and multiple faults are studied as well. The results and methods are useful for quantitative analysis of functional impacts of individual or a group of molecules on the overall performance of molecular signaling networks. © 2011 IEEE.


Habibi I.,New Jersey Institute of Technology | Emamian E.S.,Advanced Technologies for Novel Therapeutics | Abdi A.,New Jersey Institute of Technology
BMC Systems Biology | Year: 2014

Background: Intracellular signaling networks transmit signals from the cell membrane to the nucleus, via biochemical interactions. The goal is to regulate some target molecules, to properly control the cell function. Regulation of the target molecules occurs through the communication of several intermediate molecules that convey specific signals originated from the cell membrane to the specific target outputs. Results: In this study we propose to model intracellular signaling network as communication channels. We define the fundamental concepts of transmission error and signaling capacity for intracellular signaling networks, and devise proper methods for computing these parameters. The developed systematic methodology quantitatively shows how the signals that ligands provide upon binding can be lost in a pathological signaling network, due to the presence of some dysfunctional molecules. We show the lost signals result in message transmission error, i.e., incorrect regulation of target proteins at the network output. Furthermore, we show how dysfunctional molecules affect the signaling capacity of signaling networks and how the contributions of signaling molecules to the signaling capacity and signaling errors can be computed. The proposed approach can quantify the role of dysfunctional signaling molecules in the development of the pathology. We present experimental data on caspese3 and T cell signaling networks to demonstrate the biological relevance of the developed method and its predictions. Conclusions: This study demonstrates how signal transmission and distortion in pathological signaling networks can be modeled and studied using the proposed methodology. The new methodology determines how much the functionality of molecules in a network can affect the signal transmission and regulation of the end molecules such as transcription factors. This can lead to the identification of novel critical molecules in signal transduction networks. Dysfunction of these critical molecules is likely to be associated with some complex human disorders. Such critical molecules have the potential to serve as proper targets for drug discovery. © 2014 Habibi et al.; licensee BioMed Central.


Emamian E.S.,Advanced Technologies for Novel Therapeutics
Frontiers in Molecular Neuroscience | Year: 2012

Schizophrenia is a prevalent complex trait disorder manifested by severe neurocognitive dysfunctions and lifelong disability. During the past few years several studies have provided direct evidence for the involvement of different signaling pathway in schizophrenia. In this review, we mainly focus on AKT/GSK3 signaling pathways in schizophrenia. The original study on the involvement of this pathway in schizophrenia was published by Emamian et al. in 2004. This study reported convergent evidence for a decrease in AKT1 protein levels and levels of phosphorylation of GSK-3β in the peripheral lymphocytes and brains of individuals with schizophrenia; a significant association between schizophrenia and an AKT1 haplotype; and a greater sensitivity to the sensorimotor gating-disruptive effect of amphetamine, conferred by AKT1 deficiency. It also showed that haloperidol can induce a stepwise increase in regulatory phosphorylation of AKT1 in the brains of treated mice that could compensate for the impaired function of this signaling pathway in schizophrenia. Following this study, several independent studies were published that not only confirmed the association of this signaling pathway with schizophrenia across different populations, but also shed light on the mechanisms by which AKT/GSK3 pathway may contribute to the development of this complex disorder. In this review, following an introduction on the role of AKT in human diseases and its functions in neuronal and non-neuronal cells, a review on the results of studies published on AKT/GSK3 signaling pathway in schizophrenia after the original 2004 paper will be provided. A brief review on other signaling pathways involved in schizophrenia and the possible connections with AKT/GSK3 signaling pathway will be discussed. Moreover, some possible molecular mechanisms acting through this pathway will be discussed besides the mechanisms by which they may contribute to the pathogenesis of schizophrenia. Finally, different transcription factors related to schizophrenia will be reviewed to see how hypo-activity of AKT signaling pathway may impact such transcriptional mechanisms. © 2012 Emamian.


Abdi A.,New Jersey Institute of Technology | Emamian E.S.,Advanced Technologies for Novel Therapeutics
Chemistry and Biodiversity | Year: 2010

Fault diagnosis engineering is a key component of modern industrial facilities and complex systems, and has gone through considerable developments in the past few decades. In this paper, the principles and concepts of molecular fault diagnosis engineering are reviewed. In this area, molecular intracellular networks are considered as complex systems that may fail to function, due to the presence of some faulty molecules. Dysfunction of the system due to the presence of a single or multiple molecules can ultimately lead to the transition from the normal state to the disease state. It is the goal of molecular fault diagnosis engineering to identify the critical components of molecular networks, i.e., those whose dysfunction can interrupt the function of the entire network. The results of the fault analysis of several signaling networks are discussed, and possible connections of the findings with some complex human diseases are examined. Implications of molecular fault diagnosis engineering for target discovery and drug development are outlined as well. © 2010 Verlag Helvetica Chimica Acta AG.


Habibi I.,New Jersey Institute of Technology | Emamian E.S.,Advanced Technologies for Novel Therapeutics | Abdi A.,New Jersey Institute of Technology
PLoS ONE | Year: 2014

Analysis of the failure of cell signaling networks is an important topic in systems biology and has applications in target discovery and drug development. In this paper, some advanced methods for fault diagnosis in signaling networks are developed and then applied to a caspase network and an SHP2 network. The goal is to understand how, and to what extent, the dysfunction of molecules in a network contributes to the failure of the entire network. Network dysfunction (failure) is defined as failure to produce the expected outputs in response to the input signals. Vulnerability level of a molecule is defined as the probability of the network failure, when the molecule is dysfunctional. In this study, a method to calculate the vulnerability level of single molecules for different combinations of input signals is developed. Furthermore, a more complex yet biologically meaningful method for calculating the multi-fault vulnerability levels is suggested, in which two or more molecules are simultaneously dysfunctional. Finally, a method is developed for fault diagnosis of networks based on a ternary logic model, which considers three activity levels for a molecule instead of the previously published binary logic model, and provides equations for the vulnerabilities of molecules in a ternary framework. Multi-fault analysis shows that the pairs of molecules with high vulnerability typically include a highly vulnerable molecule identified by the single fault analysis. The ternary fault analysis for the caspase network shows that predictions obtained using the more complex ternary model are about the same as the predictions of the simpler binary approach. This study suggests that by increasing the number of activity levels the complexity of the model grows; however, the predictive power of the ternary model does not appear to be increased proportionally. © 2014 Habibi et al.


Habibi I.,New Jersey Institute of Technology | Abdi A.,New Jersey Institute of Technology | Emamian E.S.,Advanced Technologies for Novel Therapeutics
Conference Record - Asilomar Conference on Signals, Systems and Computers | Year: 2015

Signaling networks in human cells convey signals from the cell membrane to specific target molecules via biochemical interactions, to control a variety of cellular functions. We have modeled signaling networks as communication channels where molecules communicate with each other to transfer signals. We have defined and computed the fundamental parameters of transmission error probability and signaling capacity in signaling networks. This systematic approach can be used to understand how cell signaling errors and malfunctioning molecules may contribute to the development of complex human disorders with unknown molecular bases. © 2015 IEEE.


PubMed | Advanced Technologies for Novel Therapeutics
Type: | Journal: Frontiers in molecular neuroscience | Year: 2012

Schizophrenia is a prevalent complex trait disorder manifested by severe neurocognitive dysfunctions and lifelong disability. During the past few years several studies have provided direct evidence for the involvement of different signaling pathways in schizophrenia. In this review, we mainly focus on AKT/GSK3 signaling pathway in schizophrenia. The original study on the involvement of this pathway in schizophrenia was published by Emamian et al. in 2004. This study reported convergent evidence for a decrease in AKT1 protein levels and levels of phosphorylation of GSK-3 in the peripheral lymphocytes and brains of individuals with schizophrenia; a significant association between schizophrenia and an AKT1 haplotype; and a greater sensitivity to the sensorimotor gating-disruptive effect of amphetamine, conferred by AKT1 deficiency. It also showed that haloperidol can induce a stepwise increase in regulatory phosphorylation of AKT1 in the brains of treated mice that could compensate for the impaired function of this signaling pathway in schizophrenia. Following this study, several independent studies were published that not only confirmed the association of this signaling pathway with schizophrenia across different populations, but also shed light on the mechanisms by which AKT/GSK3 pathway may contribute to the development of this complex disorder. In this review, following an introduction on the role of AKT in human diseases and its functions in neuronal and non-neuronal cells, a review on the results of studies published on AKT/GSK3 signaling pathway in schizophrenia after the original 2004 paper will be provided. A brief review on other signaling pathways involved in schizophrenia and the possible connections with AKT/GSK3 signaling pathway will be discussed. Moreover, some possible molecular mechanisms acting through this pathway will be discussed besides the mechanisms by which they may contribute to the pathogenesis of schizophrenia. Finally, different transcription factors related to schizophrenia will be reviewed to see how hypo-activity of AKT signaling pathway may impact such transcriptional mechanisms.


Grant
Agency: National Science Foundation | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 150.00K | Year: 2013

This Small Business Innovation Research (SBIR) Phase I project will study the preparation and characterization of polymer based biodegradable nanoparticles of novel inhibitors of cell proliferation. The development of polymer-based biodegradable nanoparticles is guided by the desire to improve overall survival and quality of life by increasing the bioavailability of drug to the site of disease, containing delivery to the cancerous tissues, increasing drug solubility, and minimizing systemic side effects. We have recently discovered novel anti-cell proliferative compounds with specific and unique properties that make them an ideal treatment for solid tumors. The main aim of this study is preparation and characterization of nanoparticle formulations of our compounds. The compounds studied in this project have a high chance of success during clinical development because of the drugs are administered locally, which has very little change of producing toxicity, but also the molecular targets of the compound are proven to be safe therapeutic targets. Development of such novel formulations will allow sustained delivery of novel inhibitors of cell proliferation in the tumor site. The broader impact/commercial potential of this project: Development of novel therapeutics that could be delivered locally into tumor site is critically needed for several types of human malignancies. Successful development of nanoparticle formulations of the compounds studies in this project will, if successful, reduce healthcare costs by reducing the cost of cancer therapy and by improving the survival and quality of life for many patients under cancer chemotherapy. The nanoparticle formulations developed under the proposed studies could replace several combination chemotherapy regimens that have numerous side effects in addition to being very expensive.


Grant
Agency: NSF | Branch: Standard Grant | Program: | Phase: | Award Amount: 150.00K | Year: 2013

This Small Business Innovation Research (SBIR) Phase I project will study the preparation and characterization of polymer based biodegradable nanoparticles of novel inhibitors of cell proliferation. The development of polymer-based biodegradable nanoparticles is guided by the desire to improve overall survival and quality of life by increasing the bioavailability of drug to the site of disease, containing delivery to the cancerous tissues, increasing drug solubility, and minimizing systemic side effects. We have recently discovered novel anti-cell proliferative compounds with specific and unique properties that make them an ideal treatment for solid tumors. The main aim of this study is preparation and characterization of nanoparticle formulations of our compounds. The compounds studied in this project have a high chance of success during clinical development because of the drugs are administered locally, which has very little change of producing toxicity, but also the molecular targets of the compound are proven to be safe therapeutic targets. Development of such novel formulations will allow sustained delivery of novel inhibitors of cell proliferation in the tumor site.

The broader impact/commercial potential of this project: Development of novel therapeutics that could be delivered locally into tumor site is critically needed for several types of human malignancies. Successful development of nanoparticle formulations of the compounds studies in this project will, if successful, reduce healthcare costs by reducing the cost of cancer therapy and by improving the survival and quality of life for many patients under cancer chemotherapy. The nanoparticle formulations developed under the proposed studies could replace several combination chemotherapy regimens that have numerous side effects in addition to being very expensive.


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