Functional Interrogation of Kdm6a-Dependent Tumor Suppression during Pancreatic Cancer
Functional Interrogation of Kdm6a-Dependent Tumor Suppression during Pancreatic Cancer
批准号:
9194632
负责人:
Ian Paul Winters
金额:
$3.5万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-09-14 至 2018-09-13
关键词:
AddressAffectBiologicalBiological AssayBiologyCancer BiologyCancer BurdenCancer EtiologyCancer cell lineCell LineCessation of lifeClustered Regularly Interspaced Short Palindromic RepeatsColorectal CancerCopy Number PolymorphismDataDevelopmentDiseaseEnzymesEpigenetic ProcessEpithelialFacultyFutureGene TargetingGenesGeneticGenomicsGoalsGrowthHealthHistonesHumanIn VitroKnowledgeLeadMalignant NeoplasmsMalignant neoplasm of pancreasMediatingMesenchymalMissionMolecularMusMutagenesisMutateMutationNeoplasm MetastasisOncogenicOutcomePancreasPhenotypePlayPositioning AttributePostdoctoral FellowPrimary NeoplasmPublic HealthResearchRoleSecureStagingTP53 geneTestingTherapeuticTumor SuppressionTumor Suppressor ProteinsUnited StatesUnited States National Institutes of HealthUniversitiesWorkanticancer researchbasecancer cellcancer initiationcancer typecarcinogenesiscell motilitydesigneffective therapygene functiongenome sequencinghistone demethylaseimprovedin vivoinnovationinsightinterestmalignant breast neoplasmmigrationmouse modelnext generationnovelnovel diagnosticspalliativepancreatic cancer cellspancreatic neoplasmpancreatic tumorigenesisparalogous generesearch studytargeted treatmenttumortumor growthtumor initiationtumor progressionwhole genome
中文摘要
项目总结
英文摘要
PROJECT SUMMARY
Our limited knowledge of the biological mechanisms that lead to the initiation and progression of pancreatic
cancer represents a fundamental gap in our understanding of this disease. Without this knowledge, our ability
to rationally develop effective treatments for this disease is extremely limited. My long-term goal is to
understand the genetic mechanisms that drive pancreatic carcinogenesis. To this end, my overall objective for
this specific proposal is to determine both the cellular and molecular function of KDM6A, which has recently
been uncovered as a promising novel candidate tumor suppressor of pancreatic cancer. Two important
questions remain unanswered: 1) which stage(s) of pancreatic carcinogenesis are affected by the loss of
Kdm6a, and 2) is Kdm6a's tumor-suppressive activity dependent on its canonical function as a histone
demethylase, or is it independent of its demethylase function? The rationale for this proposal, which addresses
these questions, is that it will generate fundamental insights into the biology of pancreatic cancer, which is
predicted to surpass both colorectal and breast cancer to become the 2nd leading cause of cancer death in the
U.S. by 2020. Based on existing data, my central hypothesis is that loss of Kdm6a drives the proliferation and
metastatic proclivity of pancreatic cancer cells in a demethylase-independent manner. To address my central
hypothesis and accomplish my overall objective, I will pursue two specific aims: Aim 1) Determine the effect of
Kdm6a loss on tumor initiation, progression, and metastasis in a novel mouse model of pancreatic cancer; and
Aim 2) Uncover the role of Kdm6a demethylase-activity on its tumor-suppressive function in pancreatic cancer
cells. For Aim 1, I will use a CRISPR-based mouse model that I recently co-developed to inactivate Kdm6a
during pancreatic tumorigenesis. For Aim 2, I will perform comprehensive in vitro and in vivo assays on
Kdm6a-null pancreatic cancer cell lines re-expressing either wild type or demethylase-deficient Kdm6a to
determine whether the demethylase activity of Kdm6a is required for its tumor-suppressive function. I believe
this research strategy is innovative because it leverages unique methodological approaches to address
important questions surrounding pancreatic cancer biology that are otherwise prohibitively difficult to test. As a
result, this proposal is expected to enable novel avenues of cancer research beyond those described in this
application. The research proposed here is significant because it will strategically push forward and expand the
boundaries of our knowledge of pancreatic cancer. Ultimately, this knowledge has the potential to inform the
next generation of precisely targeted therapeutics that will reduce the burden of cancer in the United States.
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会议论文
Relating Drugs to Genotypes to Transform Precision Cancer Therapeutics with Tuba-seq - a Novel, Highly Scalable and Quantitative Preclinical Experimental Oncology Platform
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批准号:10007689
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项目类别:
-
资助金额:$113.45万
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财政年份:2020
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负责人:Ian Paul Winters
-
依托单位:
Relating Drugs to Genotypes to Transform Precision Cancer Therapeutics with Tuba-seq - a Novel, Highly Scalable and Quantitative Preclinical Experimental Oncology Platform
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批准号:10256762
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项目类别:
-
资助金额:$86.51万
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财政年份:2020
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负责人:Ian Paul Winters
-
依托单位:
海外基金