Cellular Signaling Pathways in the Regulation of Fetal Hemoglobin for Treatment of Sickle Cell Disease
调节胎儿血红蛋白治疗镰状细胞病的细胞信号通路
基本信息
- 批准号:10282012
- 负责人:
- 金额:$ 16.84万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-01 至 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:AdultAnimal ModelAuxinsAvascular necrosis of boneAwardBioinformaticsBloodCRISPR/Cas technologyCell Culture TechniquesCell LineCellsCellular biologyChemicalsClustered Regularly Interspaced Short Palindromic RepeatsComplementDevelopmentDissectionDrug TargetingEngineeringErythrocytesErythroidErythroid CellsFellowshipFetal HemoglobinFundingFutureGCN2 protein kinaseGene Expression RegulationGlobal ChangeGoalsHematologyHemeHemoglobinHemoglobinopathiesHumanIndividualInternal MedicineInternationalKidney DiseasesKnowledgeLeadMass Spectrum AnalysisMediatingMentorsModelingMolecularMolecular AnalysisMorbidity - disease rateNCI Scholars ProgramOncologyOutcome StudyPathway interactionsPatientsPediatric HospitalsPennsylvaniaPharmaceutical PreparationsPharmacologyPhenotypePhiladelphiaPhosphoric Monoester HydrolasesPhosphorylationPhosphotransferasesPhysiciansProductionProtein KinaseProtein phosphataseProteomeRegulationRegulatory PathwayResearchResearch PersonnelResidenciesResourcesRoleSamplingScientistSickle CellSickle Cell AnemiaSignal PathwaySignal TransductionStrokeSurveysSystemTechniquesTestingTherapeuticTrainingTransplantationUniversitiesUp-RegulationVocational GuidanceXenograft procedureacute chest syndromebasebeta Thalassemiacareercareer developmentcombinatorialexperiencefunctional genomicsgenetic regulatory proteingenome editingimprovedin vivoin vivo Modelinhibitor/antagonistinsightinstructormortalitymouse modelnovelnovel strategiesnovel therapeutic interventionnovel therapeuticsphosphoproteomicsresearch and developmentskillssmall moleculesynergismtranscriptometranscriptome sequencing
项目摘要
PROJECT SUMMARY/ABSTRACT
The goal of the proposed five-year training plan is the development of my independent research career as
an academic adult hematology physician-scientist studying red cell biology and hemoglobin regulation. I have
completed internal medicine residency and hematology/oncology fellowship training at the University of
Pennsylvania, and I am currently a Senior Fellow/Program Scholar who will transition in July 2021 to an
Instructor and attending physician in the Division of Hematology/Oncology at UPenn. I am specifically seeking
to develop and refine the skills that will be required for a successful career as an independent investigator,
including expertise in gene regulation, signaling pathways, functional genomics, and bioinformatics. My
overarching goal is to improve therapeutic approaches for sickle cell disease (SCD) via study of key signaling
pathways that regulate expression of the fetal form of hemoglobin. My mentor for this award is Dr. Gerd Blobel,
an internationally recognized leader in erythroid gene regulation and hemoglobin switching. To add depth and
breadth to my scientific and career guidance, I have assembled a Mentoring Committee composed of
physician-scientists from diverse and complementary fields. I will have the full resources of UPenn and the
Children’s Hospital of Philadelphia available for the completion of my research and career development goals.
The goal of this proposal is to elucidate the molecular mechanisms of PP6C, a novel regulator of fetal
hemoglobin, to improve upon current treatments for SCD and beta-thalassemia. SCD afflicts millions of people
worldwide and can lead to severe complications including acute chest syndrome, stroke, avascular necrosis of
bone, and nephropathy. Although increasing levels of fetal hemoglobin (HbF) significantly reduces cell sickling
and SCD-related morbidity and mortality, effective HbF pharmacologic induction has been an elusive goal. To
this end, I recently carried out a CRISPR-Cas9 based screen to identify additional potentially druggable
molecules to increase HbF production; this screen uncovered the protein phosphatase PP6C as a novel HbF
regulator. This proposal will explore PP6C-regulated pathways with both hypothesis-driven and unbiased
approaches and will investigate suitability of PP6C as a target for HbF induction. These objectives will be
achieved via three Specific Aims: to elucidate key mechanistic pathways in the regulation of HbF by PP6C, to
explore potential cooperativities of PP6C with other HbF regulatory pathways utilizing CRISPR-Cas12a-based
techniques; and to test the role of PP6C-mediated HbF regulation in SCD and in vivo models. The outcome of
these studies will deepen our understanding of signaling pathways that govern HbF expression and unveil new
therapeutic opportunities in SCD. Completion of these aims will consolidate my experience in models of
hemoglobin switching, further my training in bioinformatics and functional genomics, and provide the basis for a
future R01 funding proposal. These studies will leave me uniquely prepared for an independent career as a
physician-scientist with a focus on red cell biology and hemoglobinopathies.
项目总结/文摘
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Scott Alan Peslak其他文献
Scott Alan Peslak的其他文献
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{{ truncateString('Scott Alan Peslak', 18)}}的其他基金
Cellular Signaling Pathways in the Regulation of Fetal Hemoglobin for Treatment of Sickle Cell Disease
调节胎儿血红蛋白治疗镰状细胞病的细胞信号通路
- 批准号:
10592428 - 财政年份:2021
- 资助金额:
$ 16.84万 - 项目类别:
Cellular Signaling Pathways in the Regulation of Fetal Hemoglobin for Treatment of Sickle Cell Disease
调节胎儿血红蛋白治疗镰状细胞病的细胞信号通路
- 批准号:
10424557 - 财政年份:2021
- 资助金额:
$ 16.84万 - 项目类别:
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