7. PROJECT 3. REWIRING THERAPEUTIC CELLS: USER-CONTROLLED T CELLS & STEM CELLS SUMMARY Ultimately, a deeper understanding of the design principles of cellular regulatory networks should transform our ability to interface with and treat disease. In particular, our understanding of cellular control systems should allow us to engineer or modulate cellular networks so that they can be reprogrammed to carry out new or modified therapeutic functions. Thus for our third and most forward-looking project we have challenged ourselves to learn how to rewire and reprogram two particular types of medically relevant cell ? T lymphocytes (T cells) and Embryonic Stem Cells (ESCs). T cells have recently emerged as an exciting new platform for cell based therapy ? when engineered to express synthetic chimeric antigen receptors (CARs) that recognize tumor antigens, adoptively transferred T cells are able to recognize and eliminate B cell cancers. Yet, these engineered T cells are so powerful that they have significant on- and off-target toxicities. Thus, the goal of engineering user-controlled circuits in therapeutic T cells presents a real-world challenge for our ability to understand and manipulate cellular control networks.
We aim to build circuits that allow systematic control over the gating and dynamics of therapeutic T cell activation. Stem cells hold similar promise as a platform for regeneration and repair, but in order for this promise to be realized, it is critical that we gain better control over when and where differentiation occurs and what cell fates are generated. Thus we aim to apply the approaches of synthetic biology to engineer user control over the dynamics and fate outcomes of stem cell differentiation. LEAD Investigator: LIM Co-Investigators: LIM, THOMSON, KROGAN

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Specialized Center (P50)
Project #
2P50GM081879-06A1
Application #
9171160
Study Section
Special Emphasis Panel (ZGM1-BBCB-7 (SB))
Project Start
Project End
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
6
Fiscal Year
2016
Total Cost
$434,539
Indirect Cost
$160,382
Name
University of California San Francisco
Department
Type
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118
Bugaj, L J; Sabnis, A J; Mitchell, A et al. (2018) Cancer mutations and targeted drugs can disrupt dynamic signal encoding by the Ras-Erk pathway. Science 361:
Obernier, Kirsten; Cebrian-Silla, Arantxa; Thomson, Matthew et al. (2018) Adult Neurogenesis Is Sustained by Symmetric Self-Renewal and Differentiation. Cell Stem Cell 22:221-234.e8
Toda, Satoshi; Blauch, Lucas R; Tang, Sindy K Y et al. (2018) Programming self-organizing multicellular structures with synthetic cell-cell signaling. Science 361:156-162
Aranda-Díaz, Andrés; Mace, Kieran; Zuleta, Ignacio et al. (2017) Robust Synthetic Circuits for Two-Dimensional Control of Gene Expression in Yeast. ACS Synth Biol 6:545-554
Lim, Wendell A; June, Carl H (2017) The Principles of Engineering Immune Cells to Treat Cancer. Cell 168:724-740
Nissen, Kelly E; Homer, Christina M; Ryan, Colm J et al. (2017) The histone variant H2A.Z promotes splicing of weak introns. Genes Dev 31:688-701
Kim, Ji-Wook; Seo, Daeha; Lee, Jung-Uk et al. (2017) Single-cell mechanogenetics using monovalent magnetoplasmonic nanoparticles. Nat Protoc 12:1871-1889
Lechler, Marie C; Crawford, Emily D; Groh, Nicole et al. (2017) Reduced Insulin/IGF-1 Signaling Restores the Dynamic Properties of Key Stress Granule Proteins during Aging. Cell Rep 18:454-467
Wilson, Maxwell Z; Ravindran, Pavithran T; Lim, Wendell A et al. (2017) Tracing Information Flow from Erk to Target Gene Induction Reveals Mechanisms of Dynamic and Combinatorial Control. Mol Cell 67:757-769.e5
Datta, Anirban; Sandilands, Emma; Mostov, Keith E et al. (2017) Fibroblast-derived HGF drives acinar lung cancer cell polarization through integrin-dependent RhoA-ROCK1 inhibition. Cell Signal 40:91-98

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