2001 — 2002 |
Bates, Paula J |
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.) |
Nucleolin--a Novel Target For Cancer Drug Discovery @ University of Louisville
DESCRIPTION: (provided by applicant) The goal of this application is to validate nucleolin as a novel target for therapeutic intervention in cancer. The identification of nucleolin as a molecular target has resulted from the discovery of non-antisense G-rich oligonucleotides (GROs) that have profound growth inhibitory effects against many solid tumor and leukemia cell lines. There is an extensive correlation between the antiproliferative activity of the GROs and their ability to bind to nucleolin protein. Nucleolin is a multifunctional nucleolar protein critically involved in cell growth, and also present on the cell surface. Levels of nucleolin are known to be elevated in malignant cells compared to normal cells, and preliminary data indicate that strategies to target nucleolin will be tumor-selective. Although the GROs themselves have considerable therapeutic potential, delivery of oligonucleotides remains a major obstacle to their clinical use, and the development of alternative nucleolin inhibitors is desirable. The investigators have already developed screening assays that can be used to identify small molecule or peptide inhibitors of nucleolin from compound libraries. Nucleolin is also accessible to rational drug design methods, due to the availability of structural information on similar proteins. Before such extensive development studies can begin, it will be necessary to further validate nucleolin as a novel target for drug discovery. The overall aim of this proposal is therefore to demonstrate that modulation of nucleolin expression or function causes tumor- selective inhibition of cell growth. To this end, cell lines that have inducible down-regulation or overexpression of nucleolin will be developed and characterized. Antisense oligonucleotides will also be used to target inhibition of nucleolin expression. To evaluate tumor-selectivity, the relationship between cell proliferation rate, levels of nucleolin, and sensitivity to GROs, will be further explored. In addition, the mechanism by which nucleolin mediates growth inhibition will be examined by determining GRO-induced changes in nucleolin, using molecular techniques and proteomics. It is anticipated that proteomics experiments to detect changes in protein expression in GRO-treated cells will also elucidate the novel mechanism of GRO effects and will potentially identify other protein targets that participate in cell growth arrest.
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0.958 |
2004 — 2005 |
Bates, Paula J |
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.) |
A Role For Nucleolin in Malignant Transformation? @ University of Louisville
DESCRIPTION (provided by applicant): As a result of our discovery that nucleolin is the likely target of novel aptamer oligonucleotides with strong antitumor activity, we have become interested in the role of this protein in cancer biology. We have proposed that the tumor-selective effects of these aptamers occur because certain nucleolin functions are more critical for the survival of transformed cells than for normal cells. Elevated levels of nucleolin are already known to be associated with malignant progression and poor clinical prognosis in a variety of cancers. However, because the best characterized functions of nucleolin involve ribosome biogenesis, it is commonly supposed that this relationship merely reflects the higher proliferative activity of malignant cells. For this reason, the functional role of nucleolin in cancer has not been extensively studied. The central hypothesis of this proposal is that rather than being simply a marker for cancer, nucleolin overexpression actively contributes to the process of malignant transformation. This postulate is based in part on a number of recent studies that have identified new functions for nucleolin, many of which could potentially promote the development, survival, or progression of the malignant phenotype. In addition, preliminary data indicate that expression of antisense nucleolin mRNA in Hela tumor cells leads to reduced proliferation and suppression of anchorage-independent growth, whereas HeLa cell lines overexpressing nucleolin exhibit a more aggressive phenotype compared to wild type cells. The aim of the proposal is to test the hypothesis that overexpression of nucleolin can cause neoplastic transformation of normal cells in vitro and in vivo, This will be achieved by creating NIH3T3-derived cell lines with stable high level expression of nucleolin and generating transgenic mice that have prostate-targeted overexpression of nucleolin. Cell lines will be analyzed for standard features of malignancy such as altered morphology, increased proliferation, anchorage-independent growth, decreased sensitivity to apoptotic stimuli, enhanced migration, and tumorigenicity in nude mice. Transgenic mice will be examined histologically for malignant or pre-malignant changes of the prostate. Success in demonstrating that nucleolin overexpression functionally contributes to malignant transformation would open up new avenues for exploration in cancer research and firmly establish nucleolin as a novel target for therapeutic intervention.
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0.958 |
2006 — 2010 |
Bates, Paula J |
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. |
Tumor-Targeting Oligonucleotides @ University of Louisville
[unreadable] DESCRIPTION (provided by applicant): A major goal of translational cancer research is to develop targeted therapies that can specifically inhibit the expression or function of proteins that play an essential role in oncogenesis. There is considerable interest in using synthetic DNA or RNA oligonucleotides to achieve this goal because of their ability to recognize specified nucleic acid sequences or protein structures with high affinity. Several oligonucleotide-based strategies, including antisense, small interfering RNAs (siRNAs), protein-binding aptamers and immunostimulatory oligonucleotides, have produced potent anti-cancer effects in pre-clinical studies. However, clinical trials of therapeutic (antisense) oligonucleotides have been generally disappointing and this has been attributed, in part, to their inefficient uptake by cancer cells. The Principal Investigator and her collaborators have developed a novel antiproliferative oligonucleotide named AGRO100. This molecule has recently been tested in a clinical trial involving patients with advanced cancer and has demonstrated a remarkable lack of toxicity combined with promising clinical activity. Unlike most other oligonucleotides, AGRO100 is taken up efficiently and selectively by cancer cells in culture and in vivo. We hypothesize that these extraordinary properties are related to the unusual G-quadruplex structure of AGR0100 and its ability to bind specifically to a protein that is expressed at high levels on the surface of cancer cells. The long-term goal of this project is to develop oligonucleotides that are avidly and selectively taken up by cancers in vivo. Such tumor-targeting sequences could be incorporated into oligonucleotide-based therapeutics or conjugated to chemotherapy drugs in order to enhance their efficacy and reduce unpleasant side effects. In this application, we propose to elucidate the mechanism involved in the preferential uptake of AGRO100 by tumors and to identify sequence or structural motifs that lead to efficient oligonucleotide internalization by cancer cells. The first specific aim is to characterize the cellular internalization of AGRO100 and confirm the role of nucleolin in this process. The second aim is to use a SELEX approach to identify oligonucleotides (from combinatorial libraries) that have efficient and selective uptake by cancer cells. The third aim is to incorporate the optimal tumor-targeting sequences into antisense, siRNA and immunomodulatory oligonucleotides in order to determine if this leads to superior uptake and activity. [unreadable] [unreadable] [unreadable] [unreadable]
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0.958 |
2015 — 2017 |
Bates, Paula J. Krentsel, Eugene Miller, Donald M. |
U01Activity 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. |
The Excite Program: Expediting Commercialization, Innovation, Translation, & Entrepreneurship @ University of Louisville
? DESCRIPTION (provided by applicant): The overarching goal of this project is to increase the success rate and speed with which the results of basic biomedical research are translated into products that have a positive impact on human health. To do this, we propose to create a commercialization program at the University of Louisville (UofL) with a structure that is designed to overcome the many obstacles that currently impede translation. Though UofL is a relatively small institution in an IDeA state, it has invested in talent and infrastructure for translational research in order to create a pro-entrepreneurial culture. This has already paid dividends and UofL has been awarded numerous major grants, including three current COBRE awards, a Coulter Translational Partnership, the NIH Cardioprotection Consortium, the NIH-UofL RBL (a BSL-3 facility), and multiple P-/U- series grants. Moreover, UofL discoveries have led to interventions that have already benefited patients, such as a first-in- class anticancer drug, a method to prevent transplant rejection, and a protocol that has allowed paraplegic patients to stand again. Many more UofL innovations are now on their way to clinical trials, including new vaccines and minimally invasive devices to detect cancer. The proposed UofL REACH program will be known as the ExCITE Hub to reflect its function as a central resource for Expediting Commercialization, Innovation, Translation, and Entrepreneurship. The hub is designed to fulfill the goals of the FOA (RFA-OD- 14-005), but is tailored to match UofL's specific strengths and needs. In short, the university will supply a robust pipeline of diverse technologies and the infrastructure/expertise required for translational research, whereas the Hub will deliver the necessary funding, education, and access to business expertise to bridge the gap between a great idea and the marketplace. The ExCITE Hub has three major aims: (1) identify the most promising technologies and provide funding for product definition studies, (2) promote commercialization of selected products and transition to a self-sustaining ExCITE program, and (3) expand educational, experiential, and networking opportunities for stakeholders. Our approach includes innovative features: (1) a geographically focused program to expedite operations and maximize impact on the local eco-system, (2) an innovative governance structure to integrate the three main goals and avoid silos, (3) a proactive, rather than passive, approach to education, (4) a mentored technology development grant program that requires early interactions between scientists, tech transfer staff, and industry consultants, and (5) an emphasis on improving academia-industry relationships by increasing mutual understanding, ensuring robust technologies, and being responsive to industry needs. Institutional and regional commitment to the ExCITE Hub is evident from the >$3.1M in matching funds and 40 letters of support. Success in this project will have a major economic impact on the region and will speed the delivery of innovative new products to the patients that need them.
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0.958 |
2018 — 2021 |
Bates, Paula Menze, Michael Keynton, Robert (co-PI) [⬀] Kopechek, Jonathan Krentsel, Eugene |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Pfi-Rp: Development of Delivery Devices to Enable Cell Transformation or Preservation @ University of Louisville Research Foundation Inc
The broader impact/commercial potential of this PFI project will arise from the development of new devices that efficiently and uniformly transport molecules to the inside of cells. Many large or charged molecules do not easily penetrate the outer layer of cells and are not able to access the components inside the cell. This is a problem because delivery of certain molecules (including sugars, proteins, DNA, or RNA) to the inside of cells would allow better methods for modifying and storing cells. Examples of how this could be useful include a nature-inspired process for preparing freeze-dried cells so they can be stored at room temperature and rehydrated on demand, which would be useful for both research (cell lines) and medical treatments (red blood cells). If successful, these activities will increase the economic competitiveness of the United States through new product development, company formation, and training opportunities. Our research could advance public health and support national defense by improving cancer therapy and providing dried blood for military field use, space travel, and emergency preparedness. This project is also designed specifically to enhance relationships between academia and industry, and to encourage participation of women and individuals from underrepresented groups in STEM research.
The proposed project is expected to advance knowledge in many areas, including ultrasound-mediated sonoporation, microfluidics, and cryobiology. Our ultimate goal is to develop integrated ultrasound-microfluidic devices for optimal delivery of cell-impermeable molecules to a variety of cell types. Current methods are not ideal for numerous reasons including low transfection efficiency and toxicity. We plan to develop devices that can be used for the following applications: (1) intracellular delivery of cryoprotectant molecules (such as trehalose) to red blood cells or to cultured cell lines so that cells can be frozen, dehydrated, stored at ambient temperature, and then rehydrated without substantial loss of viability or function; and (2) intracellular delivery of biomolecules (DNA, RNA, or protein) to cultured cells or primary cells for use in research or therapy. Parameters to be optimized include microfluidic designs, flow rate, cryopreservation or transfection solutions, and methods for sonoporating, freezing, drying, and recovery. The success of our approach will be determined by evaluating multiple factors, such as loading, viability, and function. This is an academia-industry partnership project where university researchers and industry experts will work together to maximize the speed of development and the likelihood that the project will result in a commercially viable product.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
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1 |
2020 — 2021 |
Bates, Paula J. Dwoskin, Linda P [⬀] |
U01Activity 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. |
Kentucky Network For Innovation & Commercialization (?Kynetic?)
ABSTRACT Knowledge generated by academic research is a major source of health-related innovations. Transforming innovative discoveries into commercialized products that improve human health is a difficult process. However, all stakeholders (universities, funding bodies, pharmaceutical and medical device industries, federal and state governments and the public) have a vested interest in identifying scalable approaches that accelerate the translation of academic innovations into biomedical products. The goal of the Kentucky Network for Innovation and Commercialization (KYNETIC) is to build a Research Evaluation and Commercialization Hub (REACH) network of commercialization resources accessible across the entire Commonwealth of Kentucky to accelerate translation of academic innovations into biomedical products. To reach this goal, the following aims will be conducted: 1) establish KYNETIC?s organizational and collaborative structure; 2) Find, fund and manage product definition/development projects; 3) Provide mentoring, skills development, experiential education and networking opportunities with industry experts, entrepreneurs and investors; and 4) Devise and implement a plan to transition to a self-sustaining entity. KYNETIC will build on lessons learned from developing a regional IDeA technology transfer accelerator (at UK) and a current REACH hub (at UL). KYNETIC will be led by the University of Kentucky (UK), in partnership with the University of Louisville (UL) and the Commonwealth Commercialization Center (C3), a private 501(c)3 non-profit commercialization organization. Also, KYNETIC will include all of Kentucky?s public regional universities and community and technical college system (KCTCS). KYNETIC?s mission is to nurture innovations and academic innovators by providing funding, mentoring, education and a network of relevant expertise. Required matching funds for KYNETIC have been committed in full by Kentucky Commonwealth Economic Development (CED) and the state R1 universities. KYNETIC will be directed by a leadership team consisting of 2 academic innovators, 2 technology transfer professionals (from UK and UL) and 2 representatives from partnering entities (C3 and CED). A steering committee including the leadership team and representatives from each participating institution, an External Review Board and the NIH will review and evaluate KYNETIC projects and fund up to 13 projects/yr using an innovative ?quick kill? management strategy. Our services will be available to as many individuals as possible. Diverse role models including innovators and entrepreneurs from underrepresented groups will be sought. The proposed Kentucky-wide REACH program will leverage our collective wealth of resources, ecosystems and extensive experience to apply and expand best practices for innovator education and mentoring. The overall impact of KYNETIC will be unprecedented opportunities for collaboration and synergy, well-prepared innovators, a statewide pro-entrepreneurial culture and delivery of de-risked technologies to benefit health and overcome the state?s health disparities.
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0.919 |