Area:
Neuroscience Biology, Pharmacology
We are testing a new system for linking grants to scientists.
The funding information displayed below comes from the
NIH Research Portfolio Online Reporting Tools and the
NSF Award Database.
The grant data on this page is limited to grants awarded in the United States and is thus partial. It can nonetheless be used to understand how funding patterns influence mentorship networks and vice-versa, which has deep implications on how research is done.
You can help! If you notice any innacuracies, please
sign in and mark grants as correct or incorrect matches.
Sign in to see low-probability grants and correct any errors in linkage between grants and researchers.
High-probability grants
According to our matching algorithm, James M. Angelastro is the likely recipient of the following grants.
Years |
Recipients |
Code |
Title / Keywords |
Matching score |
2008 — 2009 |
Angelastro, James M |
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.) |
Elimination of Carcinogen-Induced Tumor Stem Cells by Atf5 Loss of Function. @ University of California Davis
[unreadable] DESCRIPTION (provided by applicant): Activating transcription factor 5 (ATF5) is highly expressed in neural stem/progenitor cells, and disappears when these cells differentiate into neurons and astrocytes. Over expression of exogenous ATF5 maintains neural stem/progenitor cells in their undifferentiated state. By contrast, loss of functional ATF5, achieved through overexpression of its dominant negative or loss of ATF5 expression by small interfering RNA, accelerates neuronal and glial differentiation. High expression of ATF5 occurs in glioblastoma tumors. Expression of dominant negative ATF5 promotes apoptosis in neural tumors, but not in non-neoplastic cells both in vitro and in vivo. Long-term objectives are to determine whether brain neoplasm, arising from environmental carcinogens, promotes transformations of neural stem cells to tumor stem cells that in turn support the growth of tumors. We propose: (1) To create brain tumors in mouse models that resemble mutations of a growth factor amplified pathway and DNA- adduct genetic lesions. (2) Show that neural stem/progenitors constitutively overexpress endogenous ATF5 resulting from neoplastic conversion. 3) Blockage of ATF5 function prevents neoplasm, and leads to cell death of pre- existing neural tumor cells and their tumor stem cells, but spares non-neoplastic cells within the same brain. (4) Finally, we will substantiate previous work to show that blocked ATF5 promotes cell cycle exit in non-neoplastic stem/ progenitor cells, but neoplasm conversion globally leads to apoptosis through prohibited cell cycle exit and/or restriction in nutrient requirements. We hope these pioneer experiments will provide future insight for therapeutic intervention aimed at targeting ATF5 to treat brain tumors in patients. PUBLIC HEALTH RELEVANCE: Despite the continuing success in treatment of cancer, there has been only limited advancement in curing neural tumors such as malignant gliomas. Recent research in our laboratory has gained insight on the mechanism by which proliferating neural stem/progenitor cells become mature neurons and glia. One of the ways is through transcription factors that bind to DNA and turn on or off genes. We found that one such transcription factor, designated ATF5, turns off genes that would lead a proliferating stem/progenitor cell to turn into either a neuron or glia. Our hypothesis is that ATF5 is permanently turned on in brain stem tumor cells and that these cells are instructed to continue to divide, and are unable to change into mature non-dividing neurons or glial cells. We found that by interfering with the function of ATF5 or by removing it from proliferating neural progenitor cells, the latter cease or slow down cell division, and are able to turn into normal neurons and glia. In a glioblastoma brain tumor cell model system, we found that interference with ATF5 function causes death of the tumor cells. Thus, ATF5 may be a potential target for therapeutic intervention and a possible treatment for brain cancer. [unreadable] [unreadable] [unreadable] [unreadable] [unreadable]
|
1 |
2014 — 2018 |
Angelastro, James M |
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. |
Using Cell-Penetrant Peptides to Target Atf5 in Mouse Glioma Models @ University of California At Davis
DESCRIPTION (provided by applicant): Brain glioma tumors, unequivocally glioblastoma multiforme (GBM), are among the most incurable forms of cancer. Such tumors are thought to arise from brain neural stem cells and progenitors that have undergone transformation into neoplasias. Neoplastic stem cells are thought to contribute to the recurrence of the glioma after chemotherapy and surgical resection. We found that activating transcription factor 5 (ATF5) is highly expressed in neural stem/progenitor cells, including cancer stem cells and GBMs. Blocking ATF5 function by dominant negative ATF5 (d/n-ATF5) or siRNA-ATF5 promotes apoptosis of glioma tumor cells, but not of non- neoplastic cells, both in vitro and in vivo. Currently, we synthesize recombinant cell penetrant d/n-ATF5 peptide that crosses the blood brain barrier, and enters into glioma cells, promoting their rapid death. The long-term objectives of our study will be to further test, as well as determine the apparent therapeutic index, of cell penetrant d/n-ATF5 toward tumor regression or full eradication in a pre-clinical approach by using different glioblastoma mouse models. Our specific aims will be to 1) Define the most effective dosing schedule for delivery of the cell penetrant d/n-ATF5 that does not harm normal tissues; test efficacy in mouse glioma/glioblastoma models by creating brain tumors through de novo transformation of progenitors and by human GBM xenografts; determine whether treatment with the peptide can bring about long-term eradication of glioblastomas; and, in the case that tumors reappear after initial treatment, whether they can again be caused to regress by application of the d/n peptide. 2) To define the responsible molecular mechanistic pathways that mediate apoptotic actions of d/n-ATF5 in glioblastoma cells. To gain insight on these pathways will enlighten how neoplasm relies on ATF5 for survival that is not observed in non-transformed cells. Knowledge of the mechanistic routes will aid in predicting and circumventing off-target effects and will explain as well as promote avoidance of potential tumor resistance toward d/n-ATF5 therapy. Finally, synergy of d/n- ATF5 with other currently employed glioblastoma therapies will be more adequately addressed with awareness of such pathways.
|
1 |