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Chak shehzad, Islamabad Campus Synopsis for the degree of MS/M.

Phil PhD

PART-I Name of the student Tahseen Ismail

Department

Biosciences

Registration No.

CIIT-FA10-RBS002

Date of Thesis Registration

Name of (i) Research Supervisor (ii) Co-Supervisor

(i) Dr. Rani Faryal

(ii)

Member of supervisory Committee 1.

2.

3.

Title of Proposal

Research Genetic analysis of Spleen Tyrosine kinase (Syk) in allergic asthma patients.

including B cells. neutrophils. is the high-affinity surface receptor for IgE. immature T cells. and airway inflammation. In the treatment of type I hypersensitivity reactions including Allergic rhinitis. and hence also important in signal transduction in these cells.Therapies targeting Syk may be more advantageous relative to drugs that inhibit a single downstream event. One of the most important kinases in the IgE signaling pathway is spleen tyrosine kinase (Syk) which has a critical function early in the signaling cascade following binding of allergen to receptor bound IgE on the mast cell.Summary of the Research Proposal Spleen tyrosine kinase (Syk) is a cytoplasmic tyrosine kinase and it is a member of the ZAP70 (ζ-chain-associated protein kinase)/Syk family of the non-receptor-type protein tyrosine kinases (PTKs). (Ulanova et al 2005). Crosslinking of receptor-bound . The present study will be conducted to observe genetic association of SYK in allergic asthma patients. Hence role of syk is very important in consideration of asthma therapy.( Denyer & Patel 2009) Asthma is a complex syndrome with many clinical phenotypes in both adults and children. asthma and anaphylaxis syk is considered as a potential pharmaceutical target because of its critical position upstream of immunoreceptor signaling complexes that regulate inflammatory responses in leukocytes. bronchial hyperresponsiveness. Its major characteristics include a variable degree of airflow obstruction. FcεRI. It is expressed in most hematopoietic cells. Introduction Allergic asthma and rhinitis are prevalent diseases in all over the world.(Mazuc et al 2008). mast cells. Inhaled allergens encounter antigen presenting cells (APC) that line the airway. The spleen tyrosine kinase (Syk) has a critical role in the regulation of such immune and inflammatory responses. marked by inflammation of the airways. and platelets (Mocsai et al 2010) . (Zhu et al 2007) (Wong et al 2004) Syk contains two SRC homology (SH2) domains and a kinase domain (Tohyama et al 2009). macrophages. and it expresses on the surface membrane of mast cells. Advances in studies of allergic mechanisms have highlighted the role of immunoglobulin E (IgE) signaling in the mast cell.

These events contribute to the development and continuation of allergic inflammation. Statement of the Problem As allergic asthma is prevalent in pakistani population like other areas of the world and spleen tyrosine kinase has a critical role in regulation of these immune responses so genetic analysis will be carried out in allergic asthma patients of Pakistani population. (Stenton et al). Syk plays an important role in the developing signal transduction events initiated after FcεRI aggregation (Costello PS 1996).Hence it can be concluded that Syk inhibition might be an attractive target for preventing allergen-induced diseases (Omer & Pamuk et al 2010). (Cheng et al 1997). the activation of which results in Ca2γ mobilization and eventually in NF-AT activation. So Syk tyrosine kinases have crucial but overlapping functions in signaling from the pre-TCR and hence in early thymocyte development. (Luskova et al 2004). During initial stage in thymocyte development. In mast cells. mast cell activation. degranulation. Important downstream targets of Syk include phospholipase Cγ1. Research Methodology Collection of blood samples: .Here we also aim to evaluate role of spleen tyrosine kinase SNPs in allergic asthma to see whether they have significant contribution in causing disease or not. and cytokine production (Masuda ES 2008).IgE by multivalent antigen starts the activation of mast cells by promoting the aggregation of FcεRI. Syk plays an essential role in activation of immune cells and lymphocyte development. Cytokine releases after the activation signal starts the cascade (Matsubara et al 2006). The Syk tyrosine kinase contains two N-terminals SH2 domains that bind phosphorylated motifs in antigen receptor subunits and are implicated in pre-T receptor signaling. this molecule is involved in regulation of multiple intracellular signaling pathways. leading to release of allergic mediators. involves expression of the pre-TCR complex and accompanying differentiation of CD42CD82 double negative (DN) cells to CD41CD81 double positive (DP) cells. after rearrangement of the beta chain genes of the T cell receptor (TCR).

Quantification of IgE level : Quantification of IgE level in serum of asthma patients will be done. Herlaar E. 145: 267–273.Blood samples from both healthy individuals and patients of allergic asthma whose skin prick test is positive and asthma is diagnosed. . Payan DG. (2009) Protein tyrosine kinase. Masuda ES. Grossbard EB. will collected from hospitals of Rawalpindi and Islamabad. (2004) Targeting Syk as a treatment for allergic and autoimmune diseases. Single stranded conformation polymorphism will be seen by running PCR product on 8% Polyacrylamide Gel Electrophoresis (PAGE) in order to observe genetic variation among asthmatic patients and healthy individuals. Genomic DNA exraction: Genomic DNA exraction from both healthy asthmatic blood samples will be carried out in laboratory. Toxicol Appl Pharmacol . Yamamura H. Masuda E. Bibliography Zhu Y. Wong BR. 221: 268–277. 13:743–762. Polymerase chain reaction: Genetic analysis and confirmation of PCR product will be done again by Agarose gel electrophoresis. DNA quantification: DNA quantification will be done by agarose gel electrophoresis. Burleson GR. Expert Opin Investig Drugs. Nelson AJ. Tohyama Y. After that Polymerase chain reaction will be carry out in order to amplify human genomic DNA. Grossbard EB. Sample size will be 120 blood samples for each of healthy and patient of allergic asthma. Syk: a key player in phagocytic cells. Clemens GR (2007) Immunotoxicity assessment for the novel Spleen tyrosine kinase inhibitor R406. J Biochem. After analysis of of PCR product.

Am J Respir Crit Care Med. Ulanova M. Pine P. Takeda K. Inhibition of Allergic Inflammation in the Airways Using Aerosolized Antisense to Syk Kinase. Yamamura H (2001). Expert Opinion in Therapeutic Targets . Denyer J. Bauer PH.130:177–186 Sadak K. Miyahara S. De´ry ER. Turner M. Dakhama A.Mocsai A. Kim M K. Li G. Miyahara N. and Befus AD. 173:56– 63 Costello PS. 13:2595–2605 Cheng AM. Puttagunta L. Nat Rev Immunol. Gelfand EW (2006) Inhibition of spleen tyrosine kinase prevents mast cell activation and airway hyperresponsiveness. 22(3): 146 Matsubara S. The Syk and ZAP-70 SH2-containing tyrosine kinases are implicated in pre-T cell receptor signaling. Walters AE. Yanagi S. Chan AC. Schmitz J (2008) Syk inhibitors as treatment for allergic rhinitis. 10:387–402. James D. Ruland J. Sorin Musat-Marcu. Boleni J. Takano T. Tybulewicz LJ. Cunningham CN. Structure and function of Syk proteintyrosine kinase. Lucas JJ. Negishi I. Anderson SJ. Schreiber AD. Loh DY and Pawson T (1997). Pulm Pharmacol Ther.. Immunology. Tentative Time Table Course Work October 2010-JUNE 2011 Research Work July 2011 – Dec 2011 0-4 months Sampling 1-4 months DNA Extraction . (2010) The Syk tyrosine kinase: a crucial player in diverse biological functions. 94: 9797–9801 Stenton GR. Gilchrist M. Merani S. The Journal of Immunology. Patel V (2009) Syk kinase inhibitors in allergic disease Drug News Perspect . 21(3):461-7.. Tybulewicz VL Critical role for the tyrosine kinase Syk in signaling through the high affinity IgE receptor of mast cells. J Biochem. Loader JE. Masuda ES. 9: 901-921 Masuda ES. Takano T (2005) Spleen tyrosine kinase (Syk) as a novel target for allergic asthma and rhinitis. Downward J. Sadak K. O Oncogene.

2-4 months Genetic analysis 4-6 months Thesis write up .

PART II Recommendation by the Research Supervisor Name Signature _____________ Date ___________ Signed by Supervisory Committee S. CGPC __________________ Date _____________________ .# Name of Committee Member 1 2 3 Designation Signature Date and Approved by Departmental graduate Advisory Committee Certified that the synopsis has been by members of GAC and considered it suitable for putting up to BASR. Secretary Graduate Advisory Committee _______________ HoD _________________ Date __________________ Date _________________ Approved by Campus Graduate Committee (CGPC) Chairman.

_________________ Not Approved on the basis of following reasons Signature _________________________ Date ________________ .PART III Dean. Faculty of ___________________________. ________________ Not Approved on the basis of following reasons Signature _____________________________ Date ____________________ Dean. ________________ Approved for placement before BASR. Graduate Studies and Research _________________ Approved for placement before BASR.

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