Sex chromosome gene regulatory networks and COPD
Sex chromosome gene regulatory networks and COPD
批准号:
10570379
负责人:
Camila Lopes-Ramos
金额:
$16.2万
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-05-01 至 2028-02-29
关键词:
AccountingAffectAgeAllelesApoptosisAwardAwarenessBiologicalBiological ProcessBlood specimenChildhood AsthmaChronic Obstructive Pulmonary DiseaseCiliaClinicalCommunitiesDataData AnalysesDevelopmentDiagnosisDiagnosticDiseaseDisease susceptibilityEpidemiologyEpigenetic ProcessExtracellular MatrixFemaleFundingFutureGene DosageGene ExpressionGene Expression ProfilingGene Expression RegulationGenesGeneticGenetic TranscriptionGenetic VariationGenotypeGenotype-Tissue Expression ProjectGoalsHealthHeterogeneityIncidenceIndividualInflammationInvestigationK-Series Research Career ProgramsKnowledgeLearningLeukocytesLinkLungLung diseasesMedicineMentored Research Scientist Development AwardMentorsMethodologyMethodsMethylationModelingMolecularMolecular BiologyMorphogenesisMultiomic DataOnset of illnessOutcomeOxidative StressPathogenesisPathway AnalysisPathway interactionsPatternPhenotypePreventiveProcessPulmonary EmphysemaPulmonary FibrosisPulmonologyQuantitative Trait LociRegulationResearchResearch PersonnelResourcesSamplingSeveritiesSeverity of illnessSex BiasSex ChromosomesSex DifferencesSiteStructure of parenchyma of lungSystems BiologyTestingTherapeuticTissuesTrainingValidationVariantWhole BloodWorkX ChromosomeX Inactivationadvanced systemaffectionbiological sexclinical practicecohortcomorbiditydetection methoddifferential expressiondisease heterogeneitydisorder riskepigenetic regulationgene regulatory networkgenetic variantgenome sequencinggenomic datainsightmaleneglectprecision medicineprogramspulmonary functionrespiratorysexsex development disorderskillssmoking exposurestudy populationtooltranscription factortranscriptomicstreatment responsewhole genome
中文摘要
项目总结/文摘
英文摘要
PROJECT SUMMARY/ABSTRACT
Despite established sex differences in COPD epidemiology and clinical manifestations, most preventive and
therapeutic strategies do not take biologic sex into consideration. This is due, in large part, to a lack of
understanding of the molecular mechanisms that drive these sex differences, as well as conceptual and
methodological gaps in incorporating sex into research and clinical practice. The involvement of X chromosome
genes in COPD has not been extensively studied, particularly incomplete X chromosome inactivation (XCI),
which causes gene dosage imbalance between sexes and sex-specific effects of genetic variation. Differences
related to sex chromosomes may allow genetic variations to have distinct functional effects in males and females.
Our hypothesis is that variations in X chromosome gene regulation affected by incomplete XCI, and X
chromosome genetic variants can help explain molecular mechanisms associated with sex differences
in COPD onset and heterogeneity. We will integrate X chromosome multi-omic data from lung and blood
samples from COPD cases and controls from three study populations (COPDGene, LTRC, and LTCOPD). We
will study sex-biased epigenetic regulation by methylation Quantitative Trait Loci (QTL) analysis (Aim 1); sex-
biased genetic regulation by expression QTL analysis (Aim 2); and sex-biased regulatory processes via gene
regulatory network analysis (Aim 3). Our investigation would be the first to model the effect of XCI into gene
regulatory networks to examine sex divergent regulatory processes and the effect of genetic variants associated
with COPD status affection, emphysema, and lung function. We expect that our network analyses will point to
genetic variants that work together to influence biological function in a sex-specific manner. Given that genes
that escape XCI can vary across individuals and tissues and have been linked to disease susceptibility, we will
examine escape genes in the context of mQTL, eQTL, and regulatory networks, and test for changes between
COPD cases and controls. Identifying variations in XCI patterns in disease will give insights into the mechanisms
associated with both disease development and sex differences in COPD. These discoveries will help us better
understand the biological mechanisms of sex differences in COPD, and provide data for future functional
validation, and sex-aware development of diagnostic and therapeutic tools. This K01 award will enable Dr.
Lopes-Ramos to build upon her existing molecular biology and transcriptomics-focused skill sets in order to learn
about epigenetics, statistical genetics, pulmonology, and integrative omic analysis and methods refinement for
sex-aware modeling and statistical comparisons. Dr. Lopes-Ramos has developed a detailed training plan and
assembled a mentoring team with complementary expertise. This K01 will allow the proposed research to be
completed successfully and will support the development of Dr. Lopes-Ramos into an independent researcher,
expert in integrative respiratory omics and network medicine.
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