University of Pennsylvania
School of Engineering and Applied Science
240 Skirkanich Hall, 210 S. 33rd Street
Philadelphia, PA 19104
Honors and Awards: NIH Director’s New Innovator Award – 2018, Burroughs Wellcome Fund Career Award at the Scientific Interface – 2018, STAT News Wunderkind Award – 2017, Merck Research Advances in Delivery Science Award, Controlled Release Society – 2017, American Association for Cancer Research (AACR) Scholar in Cancer Research – 2016, Young Investigator Council, Tissue Engineering Parts A, B, C – 2016
Research Expertise: Bioengineered Therapeutics | Devices and Drug Delivery | Biomaterials | Cellular Engineering | Molecular Engineering | Tissue Engineering | Cell Mechanics | Systems and Synthetic Bioengineering | Nanotechnology | Immunoengineering | Immunotherapy | Genome Editing | Immunoengineering | Immunotherapy
The Mitchell Lab is based in the Department of Bioengineering at the University of Pennsylvania. Our research lies at the interface of biomaterials science, drug delivery, and cellular and molecular bioengineering to fundamentally understand and therapeutically target biological barriers. We apply our research findings and the technologies developed to a range of human health applications, including cancer metastasis, immunotherapy, genome editing, cardiovascular disease, and regenerative medicine. Current research projects include: synthesis of novel biomaterials and nanoparticles for the delivery of nucleic acids (siRNA, miRNA, mRNA, CRISPR-Cas9) for cancer therapy; engineering of immune cells for immunotherapy and vaccines; investigating the influence of biomaterial chemical structure on in vivo transport to target cells and tissues using high-throughput screening platforms; and novel drug delivery technologies for tissue engineering and regenerative medicine. Mike has received an NIH National Research Service Award, the NIH Director’s New Innovator Award, and a Career Award at the Scientific Interface from the Burroughs Wellcome Fund, recognizing interdisciplinary researchers who are “bridging science fiction with reality.”
NIH Postdoctoral Fellow Chemical Engineering 2017 – Massachusetts Institute of Technology
PhD Biomedical Engineering 2014 – Cornell University
MS Biomedical Engineering 2012 – Cornell University
BE/ME Biomedical Engineering and Materials Science 2009 – Stevens Institute of Technology
Research Areas: Epigenetics, X-Chromosome Inactivation, Xist RNA, female-biased autoimmunity, epigenetic analyses using female lymphocytes, allele-specific analyses, RNA/DNA FISH, microscopy, long noncoding RNAs
The research in the Anguera laboratory focuses on maintenance of X-chromosome Inactivation in the immune system and in stem cells. They also study epigenetic mechanisms involving long noncoding RNAs during early human development and placental progenitors.
Mechanisms of X-chromosome Inactivation:
We are investigating the molecular mechanisms of X-Chromosome Inactivation, and how altered dosage of X-linked genes affects early embryonic development and contributes to sex-biased disease. We focus on the autoimmune disorder lupus, which has a strong female-bias, exhibits overexpression of X-linked immune-related genes, and involves lymphocytes. We study the epigenetic status of the inactive X in female lymphocytes from humans and mice, and have made the remarkable discovery that these cells do not maintain X-Chromosome Inactivation in the same way as other female somatic cells. We were the first to discover that the inactive X has euchromatic features in female lymphocytes, which may explain the female bias in autoimmune disorders such as lupus. We also study the dynamic mechanisms of Xist RNA localization and heterochromatin mark recruitment to the inactive X following lymphocyte activation.
Long noncoding RNAs during early human development:
We are also investigating sex-specific differences during human placental development using in vitro model systems. We discovered a novel X-linked long noncoding RNA specifically expressed in human placental progenitor cells that regulates the innate immune response.
X-chromosome Inactivation, Xist RNA, epigenetics, heterochromatin, female-biased autoimmunity, B cell development, B cell quiescence and activation, T cell quiescence and activation.
Ph.D (Biochemistry, Molecular and Cellular Biology) Cornell University, 2004
Massachusetts General Hospital / Harvard Medical School (2004 to 2012)
Fellow in Molecular Biology
415 Curie Blvd.
Clinical Research Building, Room 328,
Philadelphia, PA 19104-6148
Office: (215) 898-0398
B.Sc. (Chemistry) The Hebrew University, Jerusalem, Israel, 1973. M.Sc. (Biochemistry) Tel Aviv University, Tel Aviv, Israel, 1975. Ph.D. (Biological Chemistry) Harvard University, 1978.
Description of Research Expertise
-The Survival of Motor Neurons (SMN) complex
-Spinal Muscular Atrophy/neurogenerative disease
-Assembly and transport of RNA-protein (RNP) complexes
-High throughput screening.
Key words: RNA, RNPs (ribonucleoproteins), SMN, Spinal Muscular Atrophy, High throughput screening, neurodegneration, nuclear transport.
Description of Research
The functional forms of RNAs in cells are ribonucleoprotein (RNP) complexes, the complexes that contain RNAs and their associated RNA-binding proteins. The RNP proteins profoundly influence every aspect of the biogenesis and function of the RNAs, including their processing, transport, localization, interactions, translation, and stability. We have been particularly interested in RNA-binding proteins and the complexes they form with pre-mRNAs (hnRNAs) and mRNAs. We identified and characterized the major proteins that interact with these RNAs (hnRNPs and mRNPs) and studied them in detail. These studies led to the identification of RNA-binding domains, novel nuclear structures and transport pathways, and opened up new areas of research on important human genetic diseases, including spinal muscular atrophy (SMA) and fragile X syndrome. Over the past several years we have been involved in the discovery of a complex of proteins that forms on mRNAs in the wake of the splicing of pre-mRNAs at the site of exon ligation. This complex, the exon-junction complex (EJC), is comprised of several proteins, (including Y14, mago, RNP S1, Upf3, ALY, Srm160, eIF4A3) some of which remain associated with the mRNA after it is exported from the nucleus to the cytoplam. The EJC proteins play important roles in the export of mRNAs as well as in their translation and localization, and they serve as a marker that allows cells to define the authentic termination codon and thus detect and destroy mRNAs that contain pre-mature termination codons (nonsense-mediated decay).
We are now particularly interested in a large multi-protein complex, the Survival of Motor Neurons Protein (SMN) complex, that we described over the last few years. The SMN compex functions as an assembly machine for spliceosomal small nuclear ribonucleoproteins (snRNPs) and possibly other RNPs, in pre-mRNA splicing, and in the assembly of mRNA factories (transcriptosomes). The discovery of this kind of activity was unexpected because several RNPs have been known to have the capacity to self-assemble from purified components in vitro. In cells, however, such assembly processes would probably be inefficient and prone to inaccuracies without the assistance of the SMN complex. It casts a new light on how RNA-protein interactions, the key to post-transcriptional gene expression, are orchestrated. Some of our main objectives are to determine the complete composition, interactions, structure, and functions of the SMN complex. To assemble RNPs, the SMN complex must recognize and bring together their protein and RNA components. We are engaged in determining the specific features in the RNAs and the proteins that mediate their binding to the SMN complex. SMN is essential for viability of all cells, but reduced levels of this protein cause Spinal Muscular Atrophy (SMA), a common motor neuron degenerative disease. From studies of the SMN complex emerge new approaches for discovering potential therapeutics for SMA that we are currently pursuing.
Another major current effort is the use of lab automation and robotics for high-throughput screening (HTS) of libraries of small molecules in search of potential therapeutics for SMA. In particular, using cell-based assays we developed, we are searching for compounds that may alleviate the deficiency in the SMN protein and increase the amount of functional SMN protein in cells, as well as for compounds that may improve the survival of cells at low SMN. We have identified promising leads and are studying them further. We are also using HTS as a general approach for discovery of biologically active small molecule effectors of several pathways that we are interested in.
Please visit the lab to discuss available projects.
Jennifer Bachorik, Ph.D. – Research Associate
Mike Berg, Ph.D. – Research Associate
E. Anna Bridges – Lab Manager
Sungchan Cho, Ph.D. – Postdoctoral Fellow
Kazuhiro Fukumura, Ph.D. – Postdoctoral Fellow
Tina Glisovic, Ph.D. – Research Associate
Jennifer Jackson – Administrative Assistant
Daisuke Kaida, Ph.D. – Postdoctoral Research Fellow
Mumtaz Kasim, Ph.D. – Research Associate
Isabela Oliva, Ph.D. – Research Specialist
Anna Maria Pinto, M.D. – Postdoctoral Research Fellow
Ria Sotiriou, Ph.D. – Postdoctoral Research Fellow
Lili Wan, Ph.D. – Research Associate
Congli Wang, Ph.D. – Research Specialist
Jeongsik Yong, Ph.D. – Research Associate
Ihab Younis, Ph.D. – Research Associate
Zhenxi Zhang, Ph.D. – Research Associate
Rundong Zhang, Ph.D. – Research Specialist