2002 — 2003 |
Laywell, Eric Dion |
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.) |
Astrocytes as Multipotent Stem Cells
DESCRIPTION (Verbatim from Applicant's abstract): The present proposal is based upon our discovery that astrocytes from diverse areas of the mammalian CNS express characteristics of multipotent neural stem cells (NSCs), since they can form multipotent neurospheres in vitro. Most astrocytes lose these characteristics after a critical period of postnatal development; however astrocytes from the subependymal zone (SEZ) remain multipotent even into adulthood, and divide to maintain a large pool of neuronal precursors in this region. We propose two sets of experiments to further characterize and analyze the NSC attributes of astrocytes: 1) transplantation of astrocyte-derived neurospheres to a variety of CNS regions in order to test their ability to migrate, integrate, and generate neuronal progeny in different environments; and 2) transplantation of pre-and post-critical period astrocytes into the adult SEZ to test for the presence of factors in this region that direct astrocytes to generate neuronal progeny.
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1 |
2006 — 2007 |
Laywell, Eric Dion |
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.) |
Effect of Thymidine Analogs On Neural Stem/Progenitor Cells
[unreadable] DESCRIPTION (provided by applicant): Thymidine analogs are synthetic molecules that can substitute for thymidine when new DNA is copied during cell division. Some thymidine analogs kill cells and viruses because they act as DNA "chain terminators" by preventing the successful duplication of chromosomes. Other thymidine analogs do terminate growing DNA chains when they substitute for thymidine, and are useful as tools for "birthdating" cells because they can mark the precise time that a cell has undergone division. AZT is a chain-terminating thymidine analog that stops retrovirus replication by interfering with the enzyme reverse transcriptase, which is responsible for copying retroviral RNA into DNA. BrdU is a birthdating thymidine analog that has been used extensively in studies of neural stem cells. These proposed studies will examine both analogs in the context of adult neurogenesis. Specifically, preliminary studies indicate that both AZT and BrdU have unexpectedly deleterious effects on the ability of neural stem cells to continue dividing and making new neurons, both in vitro and in vivo. Furthermore, this effect -while initially subtle- progressively worsens as cells continue to replicate, suggesting that these thymidine analogs interfere with the enzyme telomerase which is responsible for adding DNA to specialized regions of chromosomes, the telomeres, during division. If AZT has a neurotoxic effect on neural stem cells, it is possible that antiretroviral therapy could contribute to, or exacerbate patients' neurological symptoms. Insights gained from these studies may lead to adjunct treatments that could prevent the interference of telomerase enzyme activity while preserving the therapeutic interference with viral reverse transcriptase. Additionally, establishing a role for BrdU in telomerase interference has wide scientific ramifications for the use of this molecule both in studies of neurogenesis - since BrdU incorporation may significantly alter the subsequent behavior of cells- and as a potential anti- cancer agent -since disruption of telomerase is a potential therapeutic strategy to slow tumor progression. Finally, if these analogs interfere with telomerase, a reverse transcriptase that copies RNA into DNA, they both may potentially interfere with other cellular reverse transcriptases that are important for epigenetic gene regulation, and may have severe consequences for normal cell function. [unreadable] [unreadable] [unreadable] [unreadable]
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1 |
2013 |
Laywell, Eric Dion |
R15Activity Code Description: Supports small-scale research projects at educational institutions that provide baccalaureate or advanced degrees for a significant number of the Nation’s research scientists but that have not been major recipients of NIH support. The goals of the program are to (1) support meritorious research, (2) expose students to research, and (3) strengthen the research environment of the institution. Awards provide limited Direct Costs, plus applicable F&A costs, for periods not to exceed 36 months. This activity code uses multi-year funding authority; however, OER approval is NOT needed prior to an IC using this activity code. |
Adaptive Edu Therapy For Brain Tumors @ Florida State University
DESCRIPTION (provided by applicant): There is a pressing need for new approaches in the treatment of glioblastoma multiforme (GBM). These new approaches will likely encompass both new therapeutic agents, and novel drug delivery regimens that seek to reduce toxicity and change the focus from tumor eradication to tumor management. We have shown that the synthetic thymidine analog, 5-ethynyl-2'-deoxyuridine (EdU), has profound anti-cancer activities (Ross, et al., 2011), and preliminary evidence suggests that EdU in an adaptive dosing paradigm can establish long-term stasis of xenografted human GBM tumors. Standard chemotherapy attempts to eradicate all cancer cells with drug doses that are near the maximum tolerated by the patient. This approach kills many cancer cells and can effectively prolong survival, but suffers from two serious problems: first, it nearly always selects for drug-resistant cells, allowing them to dominate the tumor; second, it contributes to poor quality of life by making patients quite ill. The theory behind adaptive therapy (borrowed from ecological population dynamics; Gatenby, et al., 2009; Gatenby, 2009; Wolkenhauer, et al., 2010) is that most continuous, high-dose drug regimens will eventually lead to the appearance of resistant cells that dominate the tumor. However, resistant cells are less fit (i.e. divide slower) than no-resistant cells in the absence of drug treatment; that is, in order to become resistant a cell must pay a cost by sacrificing other functions, and this sacrifice is manifested as a slower expansion. In the absence of drug, the non-resistant cells will outcompete and suppress the resistant cells by expanding faster and dominating the resources of the tumor. However, in the presence of high doses of drug the reverse is true. In this way tumors eventually consist only of resistant cells, and become refractory to treatment. Adaptive therapy adjusts drug dose according to the tumor response; if the tumor grows, then the dose is raised, but is lowered again when the tumor stabilizes or shrinks. The hope is to kill enough non-resistant cells to prevent the tumor from growing uncontrollably, but not so many that the constraints on the non-resistant cells are removed. In this way, the tumor will always consist of drug-sensitive cells that can -with dynamic dosage adjustments - be trimmed and managed over time, though it will likely not be completely eradicated. Here we propose to: 1) optimize an adaptive EdU protocol for the treatment of human GBM using mouse xenografts; 2) compare the efficacy of the adaptive EdU protocol to a standard therapy approach in the treatment of human GBM in mouse xenografts; and 3) assess potential negative consequences of EdU administration on the neural and hematopoietic stem cell niches. The overarching goal of these studies is improve treatment options for human glioma by testing the potential of an adaptive therapy approach using a novel chemotherapeutic candidate. In addition to introducing a new anti-cancer compound, our proposal has the potential to radically change dosing paradigms for a variety of existing treatment options.
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0.979 |