2003 |
Wang, Pin |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Nod2 Expression in Experimental Crohn's Disease @ University of Virginia Charlottesville
DESCRIPTION (provided by applicant): The aim of this project is to evaluate the role of the first Crohn's disease (CD) susceptibility gene, NOD2 in the development of chronic intestinal inflammation. There is increasing evidence that NOD2 is involved in the pathogenesis of CD from human CD susceptibility gene mapping studies and clinical genetic studies. Recent studies suggest that NOD2 expression is regulated by LPS and TNF, and NOD2 may sense bacterial LPS and activate NF-kB. Our lab has a mouse model (SAMP1/YitFc) of spontaneous chronic ileitis, which shares many features of human CD. This model provide us with a unique opportunity to investigate the abnormal expression of NOD2 in the development of chronic inflammation. To investigate NOD2 gene, first, the localization, distribution and half-life of NOD2 protein will be determined. Second, the magnitude and kinetics of NOD2 expression will be characterized at mRNA and protein levels in SAMP1/YitFc mice at different ages during the development of ileitis. Finally, the expression of Th1 cytokines and NF-kB associated genes will be explored in parallel with NOD2 expression. The overall objective of this project is to understand the function of NOD2 and associated inflammatory genes that may play a significant role in the development of Crohn's disease in order to prevent and treat this devastating disease more effectively.
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0.913 |
2006 |
Wang, Pin |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Retroviral Transduction Using Acoustic Waves @ University of Southern California
DESCRIPTION (provided by applicant): Among all types of viruses currently used in clinical trials, those based on the murine leukemia virus retroviral vectors are the most frequently used, because of its capability of stable gene integration to the chromosomes of target cells. However, retroviruses can transducer only actively dividing cells. With the relatively short half-life of retroviral particles, the probability of infectious retroviruses encountering target cells is very low because they move in a random Brownian motion. Even if they can get close to the target cells, there is the repulsion force generated from the interaction between negatively charged retrovirus envelope and cell membrane. To overcome these limitations, physicochemical approaches used to increase cell-virus contact such as addition of polycation, flow-through of virus-containing medium, spinoculation, and magnetic field have been studied and showed improved results. However, the aforementioned transduction studies were focused on anchorage-dependent cells and not easy for large-scale settings. In this study, GFP-encoding VSV-G pseudotyped retrovirus vector, which is less fragile than the un-modified retroviral vector, will be used to infect cytokine-dependent hematopoietic cell lines and primary CD34+ hematopoietic cells within ultrasonic standing wave fields generated by piezoelectric transducer and reflector. Various cytokine cocktails will be employed to stimulate the hematopoietic cells entering cell cycle and thus enhance the retroviral transduction. According to the primary acoustic radiation force and drag force, the suspended cells can be estimated to arrive at the pressure nodal planes on the 1 -2 second time scale. We speculate that the first arrived and agglomerated cells may play a role on nucleating collection of the 100 nm-sized retroviruses at the nodal planes. Several design and operating approaches are proposed to decrease the undesired acoustic and thermal streaming which might prevent the aggregation of particulates with diameter around 100 nanometer such as retroviruses. The significance of the proposed research is the engineering approach (i.e., ultrasonic standing waves fields) could be harnessed to enhance the retroviral gene delivery efficiency to hematopoietic stem/progenitor cells, which are not easy to be retrovirally transduced with current medical approaches. The success of this proposed study will provide an innovative method to the field of gene therapy.
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0.945 |
2006 — 2010 |
Wang, Pin |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Targeting Lentiviruses to Infect Chosen Cells @ University of Southern California
Gene therapy is amenable for correcting inborn errors of metabolism, as well as for the treatment of cancer and HIV.Lentiviral vectors are among the most efficient tools for gene delivery into mammalian cells. Our long-term goal is to develop a targetable gene delivery system that can transduce a specific cell type, a specific tissue or a specific organ after intravenous adminstration. Our preliminary studies have uncovered a truly targetable lentiviral vector system for gene delivery. The experimental focus of this proposal is to evaluate the therapeutic potential of this method for in vivo targeting. The first specific aim is to study the molecular mechanism of targeted infection by engineered recombinant viruses. Understanding this process should lead to identification and design of new molecules for targeting. The second specific aim is to perfect the strategy to prepare lentiviruses, which will greatly enhance the efficacy of virus preparation. The third specific aim is to explore novel molecules for targeting lentiviral vectors, which will expand our ability to manipulate lentiviruses for targeting. The fourth specific aim is to explore the utility of targeted gene delivery using antibody- and SCF-bearing lentiviruses. These studies build upon our novel finding that viruses displaying membrane-bound antibodies or stem cell factor (SCF) can specifically infect cells expressing cognate antigens or SCF receptors. Various experiments are proposed to assess the therapeutic implications of this novel targeting strategy to treat HIV and cancer in animal models. Taken together, these novel studies will enlarge the therapeutic potential of targeted gene delivery to treat a diverse range of diseases, as well as advance our undstanding of viral infection.
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0.945 |
2007 — 2009 |
Tsotsis, Theodore (co-PI) [⬀] Shing, Katherine (co-PI) [⬀] Lee, Jr., C. Ted Wang, Pin Ragusa, Gisele (co-PI) [⬀] |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
A Degree Project Approach to Engineering Education @ University of Southern California
Engineering - Chemical (53)
Chemical Engineering education is facing a growing disconnect between a curriculum focused primarily on unit operations and faculty research that has increasingly emphasized nano- and bio-technology. This discrepancy has been recognized by an NSF-sponsored Frontiers in Chemical Engineering Education initiative, recommending a move from the macroscopic, unit-operations educational approach to one in which teaching is done from the molecular point of view in a bottom-up fashion. The challenge, however, is to continue to serve the more conventional chemical and petroleum industries while instituting this change. This project team is developing a two-pronged approach of utilizing (1) a recently-created nanotechnology course-work emphasis within the Department of Chemical Engineering and Materials Science, and (2) vertically- and horizontally-integrated degree projects. The degree projects consist of emphasis-specific laboratory modules in successive Chemical Engineering courses that build upon a student's growing knowledge in their chosen emphasis, while at the same time relate the degree project to traditional areas of Chemical Engineering. Students in the Nanotechnology Emphasis, for example, synthesize nanoparticles in the Mass Balance course, examine nanoparticle interactions in Thermodynamics, fractionate nanoparticles in Separations, investigate nanoparticle catalysts in Kinetics, and examine the thermal conductivity of nanocolloids in Heat Transfer, all culminating with an independent research project in the senior year. A comprehensive assessment strategy, including an observation rubric, an efficacy scale, and a success scale, allows evaluation of how the merger of traditional Chemical Engineering subjects with advanced nanotechnology and biotechnology topics may better prepare students for today's increasingly molecular-oriented workplace.
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0.945 |
2010 — 2014 |
Wang, Pin |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Optimization of Mart-1 Tcr Gene Transfer For Anti-Melanoma Immunity @ California Institute of Technology
PROJECT 5: OPTIMIZATION OF MART-1 TCR GENE TRANSFER FOR ANTI-MELANOMA IMMUNITY ABSTRACT TCR gene transfer is a feasible approach for treating metastatic melanoma and greatly expands the scope of adoptive transfer for cancer immunotherapy. In light of the low clinical response rate to standard therapies, further optimization of this therapeutic modality is urgently needed. Our long-term goal is to optimize the components involved in TCR gene transfer so that this treatment can be translated into a reliable therapeutic modality. Our preliminary studies have identified a high affinity MART-1 TCR from a patient with an unusually high population of high affinity MART-1 specific T cells. The experimental focus of this proposal is to evaluate various strategies to improve TCR gene transfer. The first specific aim is to optimize the MART-1 TCR for an enhanced anti-melanoma response. Success of this aim will enable us to overcome the intrinsic problem of TCR mispairing and obtain an engineered MART-1 TCR with improved affinity. The second specific aim is to optimize T cells that have been modified by a MART-1 TCR to yield an enhanced anti-melanoma response, which will allow us to validate the proposed genetic modification strategies for building better T cells and develop a novel means to generate optimal MART-1 T cells in vitro for adoptive transfer. The third specific aim is to optimize a lentiviral delivery system for TCR gene transfer. Accomplishment of this aim will provide us with new versions of lentiviral vectors with superior abilities to genetically modify mature T cells, hematopoietic stem cells and embryonic stem cells. Taken together, these novel studies will contribute significantly to the further success of the next wave of investigation into TCR gene transfer.
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1 |
2012 — 2015 |
Roberts, Richard W [⬀] Roberts, Richard W [⬀] Takahashi, Terry Torao (co-PI) [⬀] Takahashi, Terry Torao (co-PI) [⬀] Wang, Pin |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Supr Peptides to Inhibit Undruggable Cancer Target (Pq18) @ University of Southern California
DESCRIPTION (provided by applicant): This application aims to demonstrate that Scanning Unnatural Protease Resistant (SUPR) peptides provide a general solution to the problem of targeting traditionally undruggable proteins. To do this, we will use mRNA display with an expanded genetic code to create a new class highly stabilized, membrane-permeant peptides that can block or modulate protein-protein interactions for two of the most important intracellular proteins conferring the oncogenic phenotype-the activated form of Ras and the Stat3 protein. Our three Specific Aims are: 1) To design stabilized SUPR peptides targeting intracellular undruggable proteins involved in cancer transformation or maintenance, 2) To characterize and enhance selected SUPR peptide functions towards cancer drug applications, and 3) To evaluate in vivo characteristics and assess the therapeutic potential of optimized SUPR peptide drug candidates for cancer treatment in mice. Overall, this project is intended to develop novel molecules as well as a general approach to target cancer-relevant proteins that have proved challenging up to this point-so much so that the proteins may be called undruggable. PUBLIC HEALTH RELEVANCE: The development of novel technologies to inhibit undruggable therapeutic cancer targets is an important public health priority. It can expand our abilities to discover new cancer drugs and improve our abilities to manage cancer. Successful completion of the proposed studies will not only offer many new treatment opportunities for cancer, but also provide new tools for cancer drug discovery.
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0.945 |
2013 — 2016 |
Eshhar, Zelig Najjar, Amer M Steiner, David Wang, Pin |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
In Situ Redirection of T Cell Specificity and Imaging of Targeted Car Expression. @ Tel-Aviv Sourasky Medical Center
DESCRIPTION (provided by applicant): Steady and promising advances have been made over the last two decades in chimeric antigen receptor (CAR)-mediated T cell (T-body) therapy. These efforts have led to major breakthroughs in the treatment of B cell malignancies and neuroblastomas in recent clinical trials. However, broader and more rapid implementation of this promising immunotherapy modality has been hindered by the labor-intensive, time-consuming, and expensive ex vivo T cell modification and expansion procedures. Furthermore, monitoring of therapeutic efficacy during the course of treatment remains suboptimal, relying on peripheral blood sampling methods that provide only a snapshot of therapeutic efficacy. To address these logistical and therapy management limitations, we are proposing to develop a combined gene delivery/imaging system based on targeting lentivectors that can specifically transduce T cells in situ with tumor-antigen specific CAR genes and herpes simplex virus-1 thymidine kinase (HSV1tk), a positron emission tomography reporter (PET) gene. This direct gene delivery approach will eliminate the need to genetically modify and expand T cells ex vivo and will provide a means of noninvasively monitoring the biodistribution, trafficking, and targeting of T-bodies to tumor tissue by PET using the nucleoside analog substrate 2'-deoxy-2'-[18F]fluoro-5-ethyl-1-?-D-arabinofuranosyl- uracil ([18F]-FEAU). Expression of HSV1tk will also enable selective ablation of transduced cells in the event of any adverse immune response. Our unique multifunctional gene delivery/imaging system is based on the central hypothesis that direct and specific in situ delivery of tumor antigen-specific CAR and HSV1tk to endogenous T cells by lentiviral vectors (via CD3-binding receptors) will redirect their specificity toward tumo cells and enable noninvasive and repetitive imaging of their targeting patterns by PET. This subset of T-bodies will further expand upon contact with target antigen. Our long-term goal is to develop an off-the-shelf lentiviral system that can be customized to express any tumor antigen-specific CAR and a PET reporter/suicide gene to inject into patients to redirect their T cells toward tumor cells while monitoring therapeutic progress by PET. As a step toward achieving our long-term goal, we are pursuing this multi-PI R01 funding mechanism to develop a prototype lentivector that will deliver erbB-2-specific CAR and HSV1tk to endogenous T cells in a mouse breast cancer model. A diverse team of investigators, headed by Professor Zelig Eshhar (PI) who pioneered CAR-based immunotherapy, will contribute expertise in the fields of CAR development, T cell targeting, and PET imaging to develop this multifunctional gene delivery/imaging therapeutic modality. Successful completion of the proposed work will have a significant impact on the implementation of cancer immunotherapy providing a larger number of patients access to promising CAR-based immunotherapy trials and expanding the application of immunotherapy to a host of malignancies.
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0.904 |