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Home > Structural and Regulatory Analysis of Angptl8 Using Computational Approaches and the Formal Verification of its Biological Regulatory Network in Insulin Resistance

Structural and Regulatory Analysis of Angptl8 Using Computational Approaches and the Formal Verification of its Biological Regulatory Network in Insulin Resistance

Thesis Info

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Author

Siddiqa, Amnah

Program

PhD

Institute

National University of Sciences & Technology

City

Islamabad

Province

Islamabad

Country

Pakistan

Thesis Completing Year

2018

Thesis Completion Status

Completed

Subject

Computational Science & Engineering

Language

English

Link

http://prr.hec.gov.pk/jspui/bitstream/123456789/12690/1/Amnah%20Siddiqa_%20Computational%20Sci%20%26%20Engg_2018_NUST.pdf

Added

2021-02-17 19:49:13

Modified

2024-03-24 20:25:49

ARI ID

1676727244878

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In this thesis, the regulation of ANGPTL8 has been deciphered at different regulatory levels using computational systems-level approaches in order to gain insights into its physiological and pathological mechanism of action. ANGPTL8 is a recently identified novel hormone and an atypical member of Angiopoietin like (ANGPTL) protein family. Dual nature of ANGPTL8 due to its ability to regulate both glucose and lipid metabolic pathways led to its emergence as a novel molecular player for the possible treatment of Diabetes Mellitus and other related metabolic disorders. Initial research efforts investigating its physiological and pathological roles partly elucidated its functional role in the regulation of metabolic machinery and insulin resistance. Thus, this thesis was designed to provide a clear understanding of the regulation of ANGPTL8 during homeostasis and compensatory insulin resistance. For this purpose, an initial check was performed to verify the association of ANGPTL8 in different murine models of compensatory insulin resistance exhibiting normoglycemia using transcriptomics data analysis. Furthermore, a systematic methodology was employed to construct a regulatory pathway of ANGPTL8 utilizing its reported interaction data. Since, none of the major pathways databases held any interaction data regarding ANGPTL8, this step was a pre-requisite for aiding future genomics studies for which pathways analysis is an integral part of the workflow. This pathway was made available to the research community through WikiPathways (an open source pathways database) and it allowed the visualization of ANGPTL8’s regulation with respect to other genes and proteins in different pathways. This pathway also aided in understanding the complex interplay of novel hormones, genes and proteins in metabolic disorders with regards to ANGPTL8. Moreover, an integrated pathways based analysis was performed on a hepatic transcriptomics data set to identify the co-expressed genes with ANGPTL8, investigate their occurrence in the known pathways, find overrepresented gene ontology classes in these genes and identify the disease linked SNPs in them. The results aided in identification of genes at different levels of regulation regarding ANGPTL8 and have implications for follow up experimental studies. This could aid in identifying additional protein partners and mutual role of these genes in leading to pathogenesis of Diabetes Mellitus and associated metabolic disorders. The signaling dynamics involved in the homeostasis and insulin resistance by ANGPTL8 were further analyzed with the formal approaches of modeling of biological regulatory networks. For this purpose, a discrete mode of ANGPTL8 associated BRN based on kinetic logic of René Thomas’ was constructed and its kinetic parameters were estimated using a model checking approach. This model was converted into a stochastic Petri net in order to simulate its time dependent dynamics. The results of these models provided insights on the role of ANGPTL8 in maintaining normoglycemia through the AKT→ FOXO, AKT→ GSK3-β and AKT→ ChREBP signaling. These results supported the hypothesis on the role of ANGPTL8 in supplementing the insulin signaling pathway during insulin resistance and aggravating the pathogenesis upon its loss. Thus, the results of this study supports its role as a glucose lowering agent and have therapeutic implications for the treatment of Diabetes Mellitus and related disorders. Furthermore, the structural characterization of ANGPTL8 was performed using several computational approaches which was verified after thorough protein-protein interaction analysis based on the available experimental knowledge and the new inferences. The finally selected structure of ANGPTL8 is based on the structure of human p85β-iSH2 domain (PDBentry:3mtt). The human p85β-iSH2 domain is one of the subunits of the regulatory domain (p85) of Phosphatidylinositol3-kinase (PI3K) protein. The protein-protein interaction analysis of ANGPTL8 with its binding partner Lipoprotein lipase revealed a model in which ANGPTL8 inhibits it by steric block of catalytic site and thus interfering with its function. This result is comparable with a similar family member ANGPTL4. In conclusion, this thesis enhanced our current understanding about the functional and structural characterization of ANGPTL8 and will further contribute to its assessment as a drug candidate.
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نیناں دے کشکول بھرے نیں

نیناں دے کشکول بھرے نیں
کہن توں لیکن درد پرے نیں

ہاواں دی انج برف پئی اے
بلدے سینے آن ٹھرے نیں

ربا ! توں تے جانوں ایں ، میں
کیہ جہے ، کیہ جہے دکھ جرے نیں

جنھاں مَیں نوں ڈوب لیا اے
جند سمندر خوب ترے نیں

جنگ تے حاکم جت لئی اے توں
ساڈے جیہڑے لوگ مرے نیں

Maulana Muhammad Ali - A Strategic Point in Indo-Muslim Politics (Comment)

‘A great man’, says Justice Oliver Wendell, Jr, ‘represents a great ganglion in the nerves of society, or to vary the figure, a strategic point in the campaign of history, and part of his greatness consists in being there’. (italic ours). And Maulana Muhammad Ali was one such nerve-centre in Indo-Muslim society during the second and third decades of the twentieth century. Indeed, he was one such strategic point in the onward march of Indo-Muslim politics that eventually found culmination and crystallization in the emergence of Pakistan. Actually no one else represented the tone, tenor and temper of the romanticist, Khilafatist era (in the 1910s and 1920s) as he did in his hectic life, his revolutionary activities his numerous discomfitures, and in his tragic death. Whether he led a hectic life, whether he took recourse to a revolutionary path, or whether he goaded himself to die a tragic death outside the frontiers of his motherland cataclysmically, in whatever he did, he, consciously or unconsciously, carried forward the campaign of Indo-Muslim history: the redemption of Islam in India and abroad. In other words, he stood, above all, for an honourable existence for Muslims in India and in the rest of the troubled Muslim world in the existential crisis that convulsed Muslim India and that world.

Impact of Investor Biases on Investment Decisions of Investors: Evidence from Pakistan

This dissertation studies the impact of investor biases on investment decisions of Pakistani stock investors. Investors take many investment decisions in stock market on daily basis but could not avoid investor biases which they are facing during this decision-making process. For this researcher carried this study and had two primary aims; first to analyze the impact ofinvestor biases on investment decisions of Pakistan stock investors and second to find which of investor biases have high, moderate, low, positive or negative, statistically significant and insignificant impact on investment decision making .The study will use Kahneman & Tversky (1979) Prospect theory as the main theoretical framework, for analyzing impact of four investor biases such as : Overconfidence bias, conservatism bias, herding effect bias and availability bias on investment decisions of investors. The study applied a mixed method approach. Quantitative data was collected through a well-defined adopted questionnaire from the respondents selected through Stratified random sampling technique. In first stage, piloting was done on the sample of 50 respondents to shortlist best questions in the questionnaire who could answer all the research questions raised in the study. After piloting and refining of questionnaire a questionnaire survey was carried out by the researcher and administered to over 462 (77% response rate) stock investor of Pakistan stock exchange (PSX) branches such as : Karachi Stock Exchange(KSE), Lahore Stock Exchange(LSE) and Islamabad Stock Exchange(ISE) on the basis of Stratified random sampling technique. After that, quantitative data was analyzed by using IBM SPSS 21 statistical software. This data analysis was carried out in two sections namely; pre and post to find the impact of different investor biases on the investment decision of Pakistani stock investors. Both descriptive and exploratory analysis were done to determine the impact of these variables in pre and post analysis. The main variables were overconfidence bias, conservatism bias, herding effect bias and availability bias consisting of seven, six, seven and six sub variables respectively. After that, qualitative data analysis was carried out through interviews technique and then through thematic analysis technique. Findings of both quantitative and qualitative data analysis in this study revealed that investor biases have different level of impact on investment decisions of PSX investors and results shows that they have statistical significance and insignificant impact, positive and negative impact, high, moderate and low impact on investment decisions of PSX investors.