哥伦比亚大学微生物学和免疫学博士后岗位
Post-doctoral fellow : Columbia University, College of Physicians and Surgeons, New York, NY10032
Employer:
Columbia University, department of microbiology and immunology
Location:
Columbia University, College of Physicians and Surgeons, New York, NY10032
Posted:
September 21, 2009
Expires:
November 20, 2009
tag(s):
Columbia University, microbiology, immunology , stem cells, postdoc
job description:
Below is a detailed description of the research performed in our laboratory. We welcome researchers who are interested in our research to join us. The qualified candidate should have a M.D. and/or Ph.D in biomedical sciences with expertise in immunology and molecular biology. Candidates with experience in working with mouse stem cells will be preferred. Interested candidates should contact Uttiya Basu (ub2121@columbia.edu) with curriculum vitae, list of publications and names and addresses of three references.
Antibodies are polypeptide complexes produced by B-lymphocytes of the immune system that identify and neutralize foreign antigens, such as bacteria and viruses. Antibodies are comprised of immunoglobulin (Ig) heavy (IgH) and light (IgL) chain polypeptides. Each protein has an N-terminal variable region that facilitates its binding to an antigen, and a C-terminal constant region that for the IgH chain is necessary to determine downstream functions. There are three somatic DNA alteration events that enable mammalian B lymphocytes to accomplish enormous antibody diversification: V(D)J recombination, class switch recombination and somatic hypermutation. Developing B cells, in the bone marrow, undergo V(D)J recombination to assemble exons encoding the IgH and IgL variable (V) regions upstream of the corresponding constant region (CH) exons. Thereafter, the newly generated B cells migrate to secondary lymphoid organs where they encounter antigens, and are stimulated to further undergo two additional Ig gene alterations, class switch recombination (CSR) and somatic hypermutation (SHM). CSR is a B cell-specific DNA rearrangement reaction that replaces the initial Ig heavy chain constant region gene (CH) exon Cμ with other downstream CH exons so that secondary isotypes (IgG, IgA etc) with different effector functions are generated. CSR occurs between the repetitive switch (S) regions that precede each of the CH genes so that the intervening DNA is deleted and the V(D)J exon is joined to a new CH gene. SHM, on the other hand, introduces point mutations into V genes at a very high rate, ultimately leading to increased antibody affinity. Though two distinct processes, CSR and SHM absolutely require transcription through the relevant Ig loci and the activity of the B cell specific protein factor Activation Induced cytidine Deaminase (AID). AID is a single-stranded DNA cytidine deaminase, whose molecular mechanism of function is highly debated. Human patients with inactivating mutations in the AID gene suffer with severe immmunedeficiency leading to Hyper-IgM syndrome (HIGM2), where as aberrant activity of AID leads to various B and T cell malignancies. Thus, the mechanism of regulation of AID activity in B cells is a major interest in our laboratory.
The important discovery of DNA mutagenic properties of AID that induce antibody diversification via CSR and SHM has opened up many questions. The four main questions that require attention are (a) How is AID predominantly targeted to V genes and switch sequences? (b) What are the mechanisms by which physiological targets of AID are repaired in a mutagenic fashion in B cells? © How do the various means of regulation of AID (transcriptional, post-transcriptional and post-translational) prevent it from acting as a pleotropic cellular mutagen? and (d) What physiological relevance and mechanism of action does AID activity have in non-B cells. One mode of AID activity regulation is via its phosphorylation at residue Serine-38 by cAMP-dependent protein kinase A. Although work from several laboratories have now unequivocally demonstrated that AID phosphorylation at Serine-38 residue has a major role in the regulation of its function and targeting to its physiological substrates, it is clear that AID is regulated by various other means that along with its phosphorylation status eventually fine-tunes its function. Using our knowledge regarding AID biology, we propose to investigate the mechanism that answers the aforementioned questions. Focus on such questions allows our laboratory to diversify into the fields of transcription, protein function regulation and DNA repair in B cells and other cell types. Furthermore, these studies should shed light on the fundamentals of genomic stability and its evolution.
Recent Publications:
1. Basu, U., ChaudhurI, J., Alpert, C., Dutt, S., Rangananth, S., Li, G., Schrum, J.P., Manis, J.P. and Alt, F.W. (2005) The AID antibody diversification enzme is regulated by protein kinase A phosphorylation. Nature, 438, 508-511.
2. Longerich, S., Basu, U., Alt, F.W., Storb U. (2006) AID in somatic hypermutation and class switch recombination. Curr. Op. In Immunology, 18, 1-11.
3. Basu, U., Chaudhuri, J., Phan, R.T., Datta, A., and Alt, F.W. (2007) Regulation of activation induced deaminase via phosphorylation In: Mechanisms of Lymphocyte Activation and Immune Regulation XI, Gupta, S., Cooper, M., Rajewsky, K., Alt, F.W., Melchers, F., Eds. New York, Springer. pp. 129-137.
4. Chaudhuri, J., Basu, U., Zarrin, A., Yan, C., Franco, S., Perlot, T., Vuong, B., Wang, J., Phan, R.T., Datta, A., Manis, J., and Alt, F.W. (2007) Evolution of the Immunoglobin Heavy Chain Class Switch Recombination Mechanism. Advances in Immunology. 94:157-214.
5. Basu, U., Franklin, A. and Alt, F.W. Post-translational regulation of activation induced deaminase. (2009) Philosophical Transactions of the Royal Society of Sciences, 364(1517):667-73.
6. Basu, U., Wang, Y., Alt, F.W. (2008) Evolution of phosphorylation-dependent regulation of Activation Induced cytidine Deaminase. Molecular Cell, 32:285-291.
7. Cheng, H.L., Vuong, B., Basu, U., Franklin, A., Schwer, B., Phan, R., Datta, A., Manis, J., Alt F.W. and Chaudhuri, J. (2009) Integrity of the AID Serine-38 Phosphorylation Site is Critical for Class Switch Recombination and Somatic Hypermutation in Mice. PNAS, 106(8):2717-22.
8. Basu, U., Franklin, A., Schwer, B., Cheng, H-L, Chaudhuri, J., Alt, F.W. (2009) Regulation of Activation-Induced Cytidine Deaminse DNA Deamination Activity in B cell by Serine-38 phosphorylation. Biochem Soc Trans., 37(Pt 3):561-8.
contact:
Candidates with experience in working with mouse stem cells will be preferred. Interested candidates should contact Uttiya Basu (ub2121@columbia.edu) with curriculum vitae, list of publications and names and addresses of three references.