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Adrian R. Krainer

Professor


Ph.D., Harvard University, 1986


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(516) 367-8417 (p)
 
Our DNA carries the instructions to manufacture all the molecules needed by a cell.  After each gene is copied from DNA into RNA, the RNA message is "spliced" - an editing process involving precise cutting and pasting.  I am interested in how splicing normally works, how it is altered in genetic diseases and cancer, and how we can correct these defects for therapy.
Adrian Krainer’s lab studies the mechanisms of RNA splicing, ways in which they go awry in disease, and the means by which faulty splicing can be corrected. In particular, they study splicing in spinal muscular atrophy (SMA), a neuromuscular disease that is the leading genetic cause of death in infants. In SMA, a gene called SMN2 is spliced incorrectly, making it only partially functional. The Krainer lab found a way to correct this defect using a powerful therapeutic approach. It is possible to stimulate SMN protein production by altering mRNA splicing through the introduction into cells of chemically modified pieces of RNA called antisense oligonucleotides (ASOs). Following extensive work with ASOs in mouse models of SMA, one such molecule, known as nusinersen or Spinraza, was taken to the clinic, and at the end of 2016 it became the first FDA-approved drug to treat SMA, by injection into the fluid surrounding the spinal cord. The Krainer lab is currently using this approach for the study of other diseases caused by splicing defects, including familial dysautonomia. In addition, they are applying antisense technology to stabilize mRNAs that are destroyed by a process called nonsense-mediated mRNA decay (NMD), both to learn about the underlying mechanisms and to develop new therapies. The Krainer lab has also worked to shed light on the role of splicing proteins in cancer. They found that the splicing factor SRSF1 functions as an oncogene, and they recently characterized the splicing changes it elicits when overexpressed in the context of breast cancer; several of these changes contribute to various aspects of cancer progression. Finally, the lab continues to study fundamental mechanisms of splicing and its regulation, and they identified novel ways in which the U1 snRNA can recognize natural 5’ splice sites that deviate from the consensus.

Nomakuchi, T. T. and Rigo, F. and Aznarez, I. and Krainer, A. R. (2016) Antisense oligonucleotide-directed inhibition of nonsense-mediated mRNA decay. Nat Biotechnol 34(2) pp. 164-166.

Anczukow, O. and Akerman, M. and Clery, A. and Wu, J. and Shen, C. and Shirole, N. H. and Raimer, A. and Sun, S. and Jensen, M. A. and Hua, Y. and Allain, F. H. and Krainer, A. R. (2015) SRSF1-Regulated Alternative Splicing in Breast Cancer. Mol Cell 60(1) pp. 105-17.

Hua, Y. and Liu, Y. H. and Sahashi, K. and Rigo, F. and Bennett, C. F. and Krainer, A. R. (2015) Motor neuron cell-nonautonomous rescue of spinal muscular atrophy phenotypes in mild and severe transgenic mouse models. Genes Dev 29(3) pp. 288-297.

Roca, X. and Akerman, M. and Gaus, H. and Berdeja, A. and Bennett, C. F. and Krainer, A. R. (2012) Widespread recognition of 5' splice sites by noncanonical base-pairing to U1 snRNA involving bulged nucleotides. Genes & Development 26(10) pp. 1098-109.

Hua, Y. and Sahashi, K. and Rigo, F. and Hung, G. and Horev, G. and Bennett, C. F. and Krainer, A. R. (2011) Peripheral SMN restoration is essential for long-term rescue of a severe spinal muscular atrophy mouse model. Nature 478(7367) pp. 123-6.

Additional materials of the author at
CSHL Institutional Repository