1990 — 1992 |
Gelmann, Edward P |
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. |
Molecular Mechanisms For Prostate Cancer Cell Growth
Prostate cancer is the second most common malignant disease among American men. There are 96,000 new cases and 26,000 deaths from prostate cancer annually. Black men in America have the highest incidence of prostate cancer of any population group in the world. The incidence among black Americans is more than twice the incidence among white Americans. Prostate cancer accounts for substantial morbidity by virtue of metastatic spread, particularly to bone, which can cause diminution in quality of life and economic productivity. More than two-thirds of prostate cancer cases present as disseminated diseases. A high proportion of disseminated prostate cancer cases are medically manageable at presentation because the cancer cells are hormone- responsive. A number of therapeutic approaches which reduce circulating androgens may cause regression or growth-arrest in these cases of prostate cancer. The cancer may be suppressed completely for up to several years, but always recurs. When it does recur it is generally hormone- unresponsive. There is no effective long-term therapy for metastatic prostate cancer which has relapsed after hormonal therapy. The purpose of the proposed work is to identify genes responsible for the progression of hormone-dependent prostate cancer to hormone-independence. A novel host/vector gene cloning system will be used to isolate cDNA clones which can confer hormone-independent growth to the hormone-dependent human prostate cancer cell line, LNCaP. The proposed work includes: 1) Construction of cDNA libraries from hormone-independent and tumorigenic cell lines. 2) Characterization of sublines of LNCaP cells for use in the host/vector system to isolate cDNA clones by phenotypic expression. 3) Isolation of cDNA clones that confer hormone-independent growth in vitro to LNCaP cells. 4) In vivo selection of cDNA clones that confer tumorigenesis to LNCaP cells. 5) Sequencing and structural characterization of cDNA clones and their expression in other cells and tissues.
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1 |
1992 — 1996 |
Gelmann, Edward 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. |
Markers For Malignant Progression in Prostate Cancer |
1 |
1992 — 1994 |
Gelmann, Edward P |
P20Activity Code Description: To support planning for new programs, expansion or modification of existing resources, and feasibility studies to explore various approaches to the development of interdisciplinary programs that offer potential solutions to problems of special significance to the mission of the NIH. These exploratory studies may lead to specialized or comprehensive centers. |
Specialized Pgm of Research Excellence/Prostate Cancer |
1 |
1994 — 2000 |
Gelmann, Edward P |
N01Activity Code Description: Undocumented code - click on the grant title for more information. |
Prostate, Lung, Colorectal &Ovarian Cancer
The Prostate, Lung, Colon-rectum and Ovary Cancer Screening Trial is designed to determine in screenees aged 60-74 years at entry whether: a. In females and males (1) screening with flexible sigmoidoscopy (60 cm sigmoidoscope) can reduce mortality from colo-rectal cancer; and, (2) screening with chest x-ray can reduce mortality from lung cancer. b. In males (1) screening with digital rectal examination plus serum prostate-specific antigen (PSA) can reduce mortality from prostate cancer; c. In females (1) screening with pelvic examination plus CA 125 and transvaginal ultrasound can reduce mortality from ovarian cancer; The secondary objectives are: (1) to assess screening variables other than mortality for each of the interventions including sensitivity, specificity, and positive predictive value; (2) to assess incidence, stage, and survival experience of cancer cases and (3) to investigate the mortality predictive value of biologic and or prognostic characterizations of tumor tissue as intermediate endpoints. This contractor will recruit and randomize to screening or control 10,000 subjects in equal gender balance. Screening will be annual for four years, except that sigmoidoscopy will be done only in the initial and last screen. Subjects will be followed for ten years from entry. A total of 148,000 subjects will be recruited by ten participating Screening Centers. The trial also includes a Data Management and Coordinating Center and a Laboratory for blood assays.
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1 |
1998 — 1999 |
Gelmann, Edward P |
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.) |
Nkx31 in Prostate Cancer
DESCRIPTION: NKX3.1 is a gene with prostate-specific expression that is homologous to the Drosophila NK homeobox gene family. NKX3.1 is highly expressed in adult prostate and at a much lower level in testis, but little or not at all in several other tissues. Levels of NKX3.1 mRNA are increased after androgen stimulation of the prostate carcinoma line LNCaP. The NKX3.1 gene map to chromosome locus 8p21 within approximately 2 megabases of NEFL, one of the most frequently deleted markers in prostate cancer. There is some variability in the frequency of 8p LOH in different series, but it may be as high as 70%. This implies that a tumor suppressor gene resides on 8p and is partially inactivated by loss of one of the two 8p alleles. The coding region of NKX3.1 is not mutated in prostate cancer tissues, but the promoter region has not bee studied. We have described a polymorphism, R52C that results in a nonconservative arginine->cysteine substitution at amino acid 52 in the NKX3.1 protein. The amino acid substitution causes altered binding to a DNA homeobox in vitro. Therefore, the polymorphism may be responsible for physiological differences in protein activity. The structure and expression of NKX3.1 will b investigated in prostate cancer. The R52C polymorphism will be evaluated for its impact on prostate cancer risk. NKX3.1 will be studied as a marker for prostate micrometastases. This is an exploratory proposal that seeks to determine the clinical relevance of NKX3.1. The applicant will pursue five specific aims: 1) characterize the 5 upstream region of NKX3.1 DNA for mutations in prostate cancer tissues; 2) determine the incidence of the R52C polymorphism in Caucasians, African Americans and Chinese; 3) using DNAs from two case control studies of prostate cancer, determine whether the R52C polymorphism influences prostate cancer risk; 4) determine if he can detect prostate cancer micrometastases in the peripheral blood by RT-PCR for NKX3.1 mRNA; 5) characterize expression of NKX3.1 protein in prostate cancer tissues by immunohistochemistry.
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1 |
1999 — 2001 |
Gelmann, Edward P |
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. |
Apoptosis in Prostate Cancer
Apoptosis, the process of programmed cell death, is a physiologic process triggered by death factor ligands acting through cell surface receptors, by DNA damage, by cell stress, or by loss of growth factor or hormone stimulation. If we could achieve activation of apoptosis during cancer treatment, then we would improve the therapeutic index by exploiting physiologic cellular signaling pathways rather than nonspecific toxic insults to cause cancer cell death. In prostate cancer treatment, induction of apoptosis is the result of both radiation and androgen deprivation, the most commonly used therapies. Recent clinical results have shown that the addition of hormone ablation to radiation therapy for locally advanced prostate cancer prolongs survival over radiation therapy alone. This beneficial therapeutic effect may have resulted from the induction of separate apoptosis pathways that enhanced cell death. DU-145 prostate cancer cells are deficient in normal retinoblastoma (RB) protein and are highly resistant to radiation-induced apoptosis. Restoration of normal RB expression in DU-145 cells conferred the ability to undergo apoptosis in response to radiation and exogenous C2- ceramide. Apoptosis was mediated by serine proteases and was not accompanied by activation of the caspase cascade. RB-mediated apoptosis was accompanied by increased expression of JUN and activation of the amino terminal JUN kinase (JNK). DU-145 cells provide a window to the study of a specific cell death pathway induced by gamma-irradiation. We have hypothesized that RB mediates a critical link between recognition of DNA damage and activation of ABL kinase to trigger the initiation of cell death. The aims of this proposal are to elucidate the details of the novel pathway for apoptosis mediated by RB and resulting in the activation of serine proteases. We will characterize in detail the cell death response mediated by serine proteases and compare it to the death response mediated by caspases. We will also test our hypothetical pathway for cell death using dominant negative mutants to block critical steps in the cell death signaling. The dominant negative constructs will block RB interaction with ABL, ABL kinase, CAP kinase, SEK1 kinase and JUN.
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1 |
1999 — 2007 |
Gelmann, Edward P |
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. |
Genetic Polymorphism in Prostate Cancer
DESCRIPTION (provided by applicant): NKX3.1 is a prostate-specific homeobox gene that maps to a region of chromosome 8p21 that is lost in up to 85% of prostate cancer cases. Although NKX3.1 does not undergo somatic mutations in prostate cancer, expression of the protein is lost with tumor progression, suggesting a role for NKX3.1 in prostate cancer pathogenesis. In Nkx3.1 mice haploinsufficiency is dominant, resulting in prostatic epithelial hyperplasia and dysplasia that worsens with age. Moreover, Nkx3.1 haploinsufficiency cooperates with loss of other suppressor genes such as Pten to enhance prostate carcinogenesis. These data suggest that loss of NKX3.1 expression may be important in pathogenesis of a large fraction of human prostate cancers and that NKX3.1 is a candidate gatekeeper gene. We described an NKX3.1 polymorphism, C154T, that resulted in an arginine to cysteine alteration of codon 52 (NKX3.1 R52C). In the initial grant period we showed that a single NKX3.1 C154T allele, present in 11% of the population, conferred an increased risk for aggressive prostate cancer. We also showed that the R52C variant altered phosphorylation at the adjacent serine 48 (S48) and that S48 phosphorylation regulated DNA binding in vitro. But NKX3.1 influences gene expression not only by DNA binding, but also by complexing with transcription factors and regulating their activity as a coactivator. Preliminary data shows that the region of amino acids 44-64 is critical for autoregulation of NKX3.1 coactivation activity, presumably by mediating binding to the C-terminus. We now will determine biochemical properties of NKX3.1 critical for its action. In Aim 1 we will perform genetic analysis of NKX3.1 to identify critical elements that regulate protein activity. In Aim 2 we will perform affinity chromatography with NKX3.1 to isolate and identify proteins that bind to NKX3.1. In Aim 3 we will identify and characterize genes whose expression is regulated by NKX3.1. In Aim 4, we will analyze tumor specimens from patients with high-grade prostate cancer to determine whether in those with the C154T polymorphic allele it is preferentially retained after loss of chromosome 8p heterozygosity.
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1 |
2000 — 2005 |
Gelmann, Edward P |
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. 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.) |
Beta Catenin in Prostate Cancer
DESCRIPTION (Applicant's Abstract): Beta-Catenin is a bifunctional molecule that mediates the connection between the cell surface adhesion molecule Ecadherin and the acting cytoskeleton and also is a partner of T cell factor (TCF) family molecules in forming a heterodimeric transcription factor that mediates signaling from Wnt receptors. beta-Catenin signaling is activated in many cancers by mutation of beta-catenin or by inactivation of beta-catenin-binding molecules. The effects of these oncogenic events are to decrease intracytoplasmic degradation and increase the availability of beta-catenin to carry out its transcriptional function. We have found mutations of the beta-catenin gene in primary prostate cancer tissues, thereby showing that beta-catenin signal transduction is activated in at least some prostate cancer cases. A second potential mechanism for beta-catenin activation in prostate cancer is loss of E-cadherin expression that occurs in approximately half of prostate cancers and is associated with poor prognosis. Our preliminary data suggest that one mechanism by which beta-catenin contributes to prostate cancer promotion and progression is by interacting with the androgen receptor and increasing transcriptional activation by androgen, the essential hormone for prostate cancer growth. Our hypothesis is that beta-catenin activation contributes to prostate cancer progression in part by augmenting androgen-driven gene transcription. This proposal focuses on determining the mechanism of molecular interaction between beta-catenin and androgen receptor. The experiments will attempt to demonstrate a direct interaction between recombinant androgen receptor and beta-catenin proteins. We will map the regions of interaction by deletion analysis and site-directed mutagenesis. We will also determine if E-cadherin binding interferes directly with the region of beta-catenin that binds to androgen receptor. These experiments will establish a linkage between steroid hormone receptor signaling and Wnt signaling. This will set the stage for more comprehensive study of the interaction between androgen action and the Wnt signaling pathway that is mediated by beta-catenin/TCFdriven transcription.
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1 |
2001 — 2002 |
Gelmann, Edward P |
U10Activity Code Description: To support clinical evaluation of various methods of therapy and/or prevention in specific disease areas. These represent cooperative programs between sponsoring institutions and participating principal investigators, and are usually conducted under established protocols. |
Cancer and Acute Leukemia Group B (Calgb) Inst Grant
DESCRIPTION (adapted from applicant's abstract): The overall objective of this project is to provide support for performance of clinical studies of the Cancer and Leukemia Group B at the Lombardi Cancer Center at Georgetown University Medical School. The LCC/GUMC is an NCI-designated Comprehensive Cancer Center. In 1988, Marc Lippman, M.D., assumed Directorship of the Lombardi Cancer Center. Under his direction, the Cancer Center was designated as a Federally Funded Cancer Center in 1989. The Cancer Center became a Federal designated "Comprehensive Cancer Center" in 1992, and the Cancer Center Support Grant was renewed in 1996 with an overall rating of "excellent to outstanding." During the previous funding period, LCC/GUMC has participated in CALGB studies as an unfunded affiliate institution of the University of Maryland Cancer Center. In March, 1997, the CALGB Board of Directors approved LCC/GUMC as a Main Member Institution. At that time, Dr. Daniel F. Hayes was named as Institutional Principal Investigator. LCC/GUMC will participate in the entire range of multimodatity clinical studies, including both therapeutic studies, correlative science studies. and companion studies of quality of life, survivorship, and cost effectiveness analyses. LCC faculty have been active in all three areas of CALGB activities: accrual, scientific leadership, and administrative tasks. As of May 1, 1997, 41 CALGB protocols were active at LCC/GUMC. A total of 129 patients have entered CALGB studies since LCC entered CALGB in 1990, with 78 of these during this funding period (1993-1996). Accrual has increased over the last three years: 1994, 10 patients; 1995, 26 patients, and 1996, 31 patients. 17 percent of these patients were from minority populations, and 69 percent of patients entered onto CALGB trials were women. A recent audit by CALGB rated LCC as "Acceptable." Several initiative are being used to increase accrual at LCC, including recruitment of onsite clinical faculty committed to clinical trials, organization of a highly coordinated Clinical Research Management Office, development of a clinical Research Consortium of off-site affiliates. and development of a Patient Accession Core Project. Lombardi has a major program to increase accrual of minorities and women to clinical trials, coordinated by the Associate Director of the Cancer Center, Dr. John Kemer. It is estimated that LCC will accrue 95 patients/year to CALCB therapeutic and companion studies. LCC faculty are already leaders in CALGB, with 12 cadre committee members, two of whom are Committee Chairs (Dr. Hayes, Solid Tumor Correlative Science; Dr. Raymond Weiss, Audit). Five faculty members are Study Chairs for 11 active CALGB trials or companion studies. Two faculty have two concepts under review that are likely to open in the next twelve months. Because of the depth of scientific accomplishments of the LCC faculty, it is anticipated that many more will assume leadership roles within CALGB now that LCC/GUMC has Main Member Status. Three faculty have had administrative roles, including Dr. Raymond Weiss who started and has been the only Chair of the Audit Committee. The LCC research infrastructure for clinical and translational science is substantial, and LCC faculty are expected to provide leadership in developing clinical and correlative science studies during the next funding cycle. In summary, with Main Membership status and maturation of the Cancer Center, the LCC is expected to become one of the leading institutions within the CALGB during the next five years.
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1 |
2003 — 2006 |
Gelmann, Edward P |
U10Activity Code Description: To support clinical evaluation of various methods of therapy and/or prevention in specific disease areas. These represent cooperative programs between sponsoring institutions and participating principal investigators, and are usually conducted under established protocols. |
Cancer and Leukemia Group B
[unreadable] DESCRIPTION (provided by applicant): The overall objective of this project is to provide support for the performance of clinical studies of the Cancer and Leukemia Group B at the Lombardi Cancer Center at Georgetown University Medical School. The LCC/GUMC is an NCI-designated Comprehensive Cancer Center. Kevin Cullen, M.D. was appointed Acting Director of the Cancer Center in February 2001. In March 1997, the CALGB Board of Directors approved LCC/GUMC as a main member institution. LCC/GUMC participates in the entire range of multimodality clinical studies including therapeutic studies, correlative science studies, and companion studies of quality of life, survivorship, and cost effectiveness analyses. LCC faculty members have been active in all three areas of CALGB activities: accrual, scientific leadership, and administrative tasks. At the present time, 42 CALGB protocols are active at GUMC/LCC. During the period from 1998-2002, 282 patients have been entered onto CALGB or Intergroup trials. LCC/GUMC faculty members are represented on 10 Committees or Working Groups. Two LCC/GUMC faculty members served as study chairs and two faculty members participated in CALGB audits. It is anticipated that LCC/GUMC investigators will continue their activities in the CALGB and new/young faculty members will become involved in the scientific endeavors of the group as they grow in their careers. A recent merger of Georgetown University Medical Center with the nonprofit MedStar Health Network has allowed the establishment of a Network-wide IRB. Because of centralized clinical trials management and approval, CALGB accrual should continue to increase: luring the next funding period. [unreadable] [unreadable] [unreadable]
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1 |
2008 — 2013 |
Gelmann, Edward P |
P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. |
Crmo- Clinical Research Management Office @ Columbia University Health Sciences
Administrator; Adverse Experience; Adverse event; Amendment; Bio-Informatics; Bioinformatics; Biostatistics Shared Resource; Budgets; CCSG; Cancer Center; Cancer Center Support Grant; Cancers; Clinical; Clinical Data; Clinical Research; Clinical Research Associate; Clinical Study; Clinical Trials; Clinical Trials Informatics Support System; Clinical Trials Informatics System; Clinical Trials Information Management System; Clinical Trials, Unspecified; Communication; Compatible; Conduct Clinical Trials; Consent Documents; Consent Forms; Core Grant; DSM; Data; Data Banks; Data Bases; Databank, Electronic; Databanks; Database, Electronic; Databases; Diagnostic and Statistical Manual; District of Columbia; Documentation; Drugs; Ensure; Ethics Committees, Research; Funding; Goals; Grant; Grants, Peer Review; Guidelines; Head; Herbert Irving Comprehensive Cancer Center; IRBs; IT Systems; Industry; Informatics; Information Systems; Information Technology Systems; Informed Consent Documents; Informed Consent Forms; Infrastructure; Institutional Review Boards; Internet; Investigators; Malignant Neoplasms; Malignant Tumor; Mediation; Medical center; Medication; Modeling; Monitor; Negotiating; Negotiation; Nursing Research; Office Management; Office of Management; Operation; Operations Research; Operative Procedures; Operative Surgical Procedures; P30 Grant; Peer Review; Peer Review Grants; Pharmaceutic Preparations; Pharmaceutical Preparations; Procedures; Process; Protocol; Protocols documentation; Purpose; Quality Control; Range; Reaction; Reporting; Research; Research Activity; Research Ethics Committees; Research Infrastructure; Research Personnel; Research Proposals; Researchers; Resource Sharing; SWOG; Southwest Oncology Group; Supervision; Surgical; Surgical Interventions; Surgical Procedure; Systems, Data; Training; Universities; WWW; Washington, D.C.; Washington, DC; Work; clinical data repository; clinical data warehouse; clinical investigation; clinical translational research system; data management; data repository; drug development; drug/agent; experience; malignancy; member; neoplasm/cancer; quality assurance; relational database; surgery; web; world wide web
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0.948 |
2008 — 2013 |
Gelmann, Edward P |
P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. |
Protocol Specific Research Resource @ Columbia University Health Sciences
The Herbert Irving Comprehensive Cancer Center participates in a wide range of innovative, feasibility or proof of principle trials originating from its research programs and initiated by institutional Pis. Enrollment in these studies has been maintained throughout the last grant period. The conduct of these studies is supported by research nursing and data management provided by the Clinical Research Management Office (CRMO). Research Nursing focuses solely on the eligibility, consenting and management of patients on clinical trials. In addition to its participation in the scope of high-priority clinical trials, Herbert Irving Comprehensive Cancer Center has conducted a series of innovative phase I trials of cancer vaccines and immunotherapy that have provided important information on the mechanisms and clinical efficacy of these agents. There is an increasing emphasis on interaction between basic science and clinical research as exemplified by ongoing translational studies in breast cancer and lymphoma. Expanded support for our participation in high priority and innovative trials is requested. The projected operating budget for Protocol Specific Research Support is $352,247, of which we are requesting 100% support from the CCSG.
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0.948 |
2012 — 2015 |
Gelmann, Edward P |
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. |
Role of the Dna Damage Response in Prostate Cancer Initiation @ Columbia University Health Sciences
This project investigates the role of NKX3.1 in protection against DNA damage in the prostate epithelium, which may provide a key mechanism for its function in tumor suppression, NKX3.I is a prostate specific homeobox gene located on 8p21, the target for the most frequent chromosomal loss in human prostate cancer. NKX3.I is also a tumor suppressor for which reduced protein expression is sufficient to deregulate prostate epithelial cell growth and cause Intraepithelial neoplasia; moreover, Nkx3.1 haploinsufficiency results in prostate epithelial dysplasia in mice. Consistent with its role as a tumor suppressor in human prostate cancer, we have shown that an Inactivating mutation In the NKX3.I homeodomain cosegregates with early onset prostate cancer in a prostate cancer family. In recent studies, we have shown that NKX3.1 enhances cell survival after DNA damage and affects the earliest events in recognition of DNA breaks, including formation of YH2AX foci and phosphorylation of ATM. Based on our hypothesis that a key mechanism by which NKX3.1 loss contributes to tumor initiation is through its impact on the DNA damage response, our studies will define the mechanistic role of NKX3.I in the DNA damage response in vitro, as well as its impact on DNA damage in vivo. We also will determine whether NKX3.I mediates the susceptibility of prostate cells to formation of the characteristic TMPRSS2- ERG chromosomal rearrangement that occurs in approximately 50% of prostate cancers. Taken together, our three aims will delineate the role of NKXS.I in the DNA damage response in distinct contexts, thereby providing a comprehensive investigation of this key mechanism of tumor suppression. In Aim 1, our experiments will define the dynamics of the functional interaction between NKX3.1 and ATM, which occurs within minutes of DNA damage. In Aim 2, we will determine whether Nkx3.I gene copy number affects the DNA damage response in vivo in the prostate epithelium, and particularly in prostate epithelial stem cells. Finally, in Aim 3, using unique lines of LNCaP cells that we have derived, we will determine whether NKX3.1 affects the frequency of TMPRSS2-ERG gene rearrangements. These proposed studies will be highly integrated with the overall program project. Notably, the experiments in Aim 2 include quantitative immunostaining analyses in collaboration with Core A, the work in Aim 2 on the prostate stem cells will be performed in collaboration with Michael Shen (Project 1), and the entirety of this project is linked to the molecular analyses of Nkx3.1 in cellular senescence by Cory Abate-Shen (Project 2).
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0.948 |