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Principal Investigator: Laurie Ann Rumker
Organization: HARVARD MEDICAL SCHOOL
Fiscal Year: 2024
Award: $46,918
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary/Abstract
Tuberculosis (TB) remains the global leading cause of death from an infectious agent. Understanding
why some patients present with early symptoms while others develop latent infections is critical for combating
this illness. While environmental factors are known to elevate the risk of early progression, a recent Genome
Wide Association Study revealed that host genetic factors also play a role, with early progression heritability
near 20%. However, TB genetics studies focusing on Europeans, which have dominated the field, suffer from
linkage disequilibrium obscuring causal loci and fail to center on the populations who suffer most from TB. By
contrast, this project will focus on a population from Lima, Peru with high TB burden and admixed ancestry,
which will reveal a broader range of genetic variants and enable more specific mapping of impactful loci. Early
progression risk is likely dictated by the immune response, the primary host-pathogen interface. Therefore,
using transcriptional profiling of monocytes (in bulk) and T cells (as single cells) in combination with genotyping
and environmental covariate data, the objective of this project is to characterize immune phenotypes altered by
genomic background that influence TB progression risk. Specifically, this project will: Aim 1) identify gene
expression immune phenotypes influenced by genetic ancestry, Aim 2) create a novel single-cell analysis
method and use it to identify cell population immune phenotypes influenced by genetic ancestry, and Aim 3)
identify specific genomic variants that alter immune phenotypes and impact TB progression risk. If successful,
this work will elucidate genomic mechanisms influencing TB infection outcomes and deepen our understanding
of immune physiology in a Peruvian population. Knowledge of genetic factors that prevent early progression
can inform the development of therapeutics and vaccines. This work will also produce a powerful method for
association testing in single cell datasets, Covarying Neighborhood Analysis, that can define with great
flexibility and granularity cell populations whose abundance is altered by a clinical phenotype of interest.
Through the fellowship training plan, the applicant will develop: expertise in complex trait genetics,
fluency in the application of and development of bioinformatic methodologies, an understanding of how social
and environmental factors also contribute to infectious disease outcomes, and familiarity with immune
physiology and clinical aspects of infectious disease management. An ideal training environment of close
mentorship by an expert in complex trait genetics of immune-mediated diseases and single-cell methods
development, plus support from a network of advisors with complementary scientific expertise and career
experience in academic medicine, in combination with exposure to relevant coursework and meetings, will
enable the applicant to thrive in this program of study. At the conclusion of this fellowship, the applicant will be
poised to tackle critical problems in computational immune genetics with applications to infectious diseases
and global health, and to bridge the clinical and computational worlds through a career in academic medicine.
Terms: <Accounting><African ancestry><African descent><Automobile Driving><Bio-Informatics><Bioinformatics><Blood monocyte><Body Tissues><Cause of Death><Cell Body><Cells><Cellular Immune Function><Cessation of life><Clinical><Communicable Diseases><Complex Genetic Trait><Data><Data Set><Death><Development><Disease><Disease Management><Disease Outcome><Disorder><Disorder Management><Environment><Environmental Factor><Environmental Risk Factor><European><European ancestry><Exposure to><Familiarity><Fellowship><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Funding><GWA study><GWAS><Gene Expression><Gene Expression Monitoring><Gene Expression Pattern Analysis><Gene Expression Profiling><Gene variant><Genes><Genetic><Genetic study><Genomics><Genotype><Haplotypes><Heritability><Immune><Immune response><Immunes><Immunological response><Immunomodulation><Individual><Infection><Infectious Agent><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Inflammatory><Knowledge><Light><Link><Linkage Disequilibrium><M tuberculosis infection><M. tb infection><M. tuberculosis infection><M.tb infection><M.tuberculosis infection><MTB infection><Maps><Marrow monocyte><Mediating><Mediation><Medicine><Mentorship><Messenger RNA><Methodology><Methods><Mycobacterium tuberculosis (MTB) infection><Mycobacterium tuberculosis infection><NIAID><National Institute of Allergy and Infectious Disease><Negotiating><Negotiation><Neighborhoods><Outcome><Pathway interactions><Patients><Persons><Peru><Peruvian><Phenotype><Photoradiation><Physiology><Population><Research><Risk><Source><Symptoms><T-Cells><T-Lymphocyte><TB infection><Testing><Therapeutic><Therapeutic Effect><Tissues><Training><Transcript Expression Analyses><Transcript Expression Analysis><Tuberculosis><Vaccines><Validation><Variant><Variation><Work><allele variant><allelic variant><analyze gene expression><career><cell type><clinical phenotype><cohort><developmental><differential expression><differentially expressed><disseminated TB><disseminated tuberculosis><driving><environmental risk><experience><flexibility><flexible><flow cytophotometry><gene expression analysis><gene expression assay><genetic variant><genome wide association><genome wide association scan><genome wide association studies><genome wide association study><genomewide association scan><genomewide association studies><genomewide association study><genomic variant><genotyped patients><global gene expression><global health><global transcription profile><host response><immune function><immune modulation><immune regulation><immune system response><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><improved><infection due to Mycobacterium tuberculosis><infectious organism><interest><latent infection><mRNA><mRNA seq><mRNA sequencing><mRNA-seq><mRNAseq><meeting><meetings><method development><monocyte><novel><pathogen><pathway><power analysis><prevent><preventing><programs><progression risk><resilience><resilient><simulation><single cell analysis><social factors><therapeutic agent development><therapeutic development><thymus derived lymphocyte><transcriptional differences><transcriptional profiling><transcriptome><tuberculosis infection><tuberculous spondyloarthropathy><vaccine strategy><validations><whole genome association analysis><whole genome association studies><whole genome association study>