B. Abstract and Specific Aims The goals of our center are to 1) elucidate the mechanical biology of T cells 2) use this understanding of T cell mechanical biology to develop novel T cell culture systems and engineered T cells for improved therapeutics. Adoptive immunotherapy overcomes many obstacles that limit vaccine strategies, by adoptively transferring T cells with controlled antigenic specificity. In addition, ex vivo culture of T cells allows for the generation of large numbers of T cells, which is of utmost importance in the face of T cell deficiencies in cancer. A major current challenge in adoptive immunotherapy is to control self-renewal potential of T cell, often referred to in immunology as "memory", as it allows the immune system to maintain a higher frequency of T cells specific for pathogens encountered earlier. Another issue is self-renewal capacity in effector populations such as Th17 CD4 cells that are high effective in adoptive immunotherapy models. Hence, by engineering this property into T cells used in adoptive immunotherapy, both the immediate and long-term effects of therapy could be improved. Our NDC hypothesized that the IS integrates chemical and mechanical signals to determine the course of T cell differentiation. A major goal of our center is thus to improve immunotherapy by controlling the phenotype and function of ex vivo expanded T cells and in scalable numbers. We will focus on immunotherapy of cancers including both leukemias and solid tumors. Besides using adoptive immunotherapy to selectively and directly attack the tumor or tumor stroma, immunotherapy can be used to protect the patient from immunopathology resulting from treatment efforts. During treatment of leukemia by hematopoietic cell transplant (HCT), which aims at reconstituting the recipient with hematopoietic and immune cells post chemotherapy, donor T cells can cause graft-versus-host-disease (GVHD) - a significant source of morbidity and mortality post-HCT. Current approaches to prevent GVHD, which rely on the use of conventional drugs, and often lead to immunodeficiency, are not satisfactory and new GVHD preventive approaches are clearly needed. Therefore, within our goal of improving patient survival and quality of life, we also plan to make use of regulatory T cells (Tregs) to protect patients from the GVHD toxic effect by modulating Treg function and potency.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Development Center (PN2)
Project #
5PN2EY016586-10
Application #
8523877
Study Section
Special Emphasis Panel (ZEY1-VSN (20))
Program Officer
Fisher, Richard S
Project Start
2004-09-30
Project End
2015-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
10
Fiscal Year
2013
Total Cost
$800,000
Indirect Cost
$65,530
Name
New York University
Department
Pathology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Mayya, Viveka; Neiswanger, Willie; Medina, Ricardo et al. (2015) Integrative analysis of T cell motility from multi-channel microscopy data using TIAM. J Immunol Methods 416:84-93
Renfrew, P Douglas; Craven, Timothy W; Butterfoss, Glenn L et al. (2014) A rotamer library to enable modeling and design of peptoid foldamers. J Am Chem Soc 136:8772-82
Choudhuri, Kaushik; LlodrĂ¡, Jaime; Roth, Eric W et al. (2014) Polarized release of T-cell-receptor-enriched microvesicles at the immunological synapse. Nature 507:118-23
Bashour, Keenan T; Gondarenko, Alexander; Chen, Haoqian et al. (2014) CD28 and CD3 have complementary roles in T-cell traction forces. Proc Natl Acad Sci U S A 111:2241-6
Bashour, Keenan T; Tsai, Jones; Shen, Keyue et al. (2014) Cross talk between CD3 and CD28 is spatially modulated by protein lateral mobility. Mol Cell Biol 34:955-64
Guedan, Sonia; Chen, Xi; Madar, Aviv et al. (2014) ICOS-based chimeric antigen receptors program bipolar TH17/TH1 cells. Blood 124:1070-80
Kumari, Sudha; Curado, Silvia; Mayya, Viveka et al. (2014) T cell antigen receptor activation and actin cytoskeleton remodeling. Biochim Biophys Acta 1838:546-56
Zhang, Xian; Moore, Simon W; Iskratsch, Thomas et al. (2014) N-WASP-directed actin polymerization activates Cas phosphorylation and lamellipodium spreading. J Cell Sci 127:1394-405
Lao, Brooke Bullock; Drew, Kevin; Guarracino, Danielle A et al. (2014) Rational design of topographical helix mimics as potent inhibitors of protein-protein interactions. J Am Chem Soc 136:7877-88
Youngs, Noah; Penfold-Brown, Duncan; Bonneau, Richard et al. (2014) Negative example selection for protein function prediction: the NoGO database. PLoS Comput Biol 10:e1003644

Showing the most recent 10 out of 111 publications