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Employing Single-Nucleus RNA-Seq to Uncover Genetic Factors of Alzheimer Disease.
Employing Single-Nucleus RNA-Seq to Uncover Genetic Factors of Alzheimer Disease.

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자료유형  
 학위논문
Control Number  
0017162703
International Standard Book Number  
9798383573648
Dewey Decimal Classification Number  
574
Main Entry-Personal Name  
Brase, Logan.
Publication, Distribution, etc. (Imprint  
[S.l.] : Washington University in St. Louis., 2024
Publication, Distribution, etc. (Imprint  
Ann Arbor : ProQuest Dissertations & Theses, 2024
Physical Description  
214 p.
General Note  
Source: Dissertations Abstracts International, Volume: 86-02, Section: B.
General Note  
Advisor: Harari, Oscar;Karch, Celeste M.
Dissertation Note  
Thesis (Ph.D.)--Washington University in St. Louis, 2024.
Summary, Etc.  
요약Alzheimer's disease (AD) stands as a daunting global health challenge, affecting millions of individuals worldwide. This burden will only intensify with an aging global population. Despite significant advances in understanding AD, further exploration is needed to enhance the development of treatments and therapeutics. Particularly, I am interested in identifying the molecular pathways involved and the cell types mediating the etiology of AD. This work underscores the ability of single nucleus RNA-seq to investigate these pathways at the cell-type level and mitigate many of the hurdles limiting the successful development of treatments for AD, including genetic heterogeneity and translation of discoveries in model systems to humans. Through Genome-Wide Association Studies (GWAS), numerous critical genetic loci influencing disease risk and pathological development have been identified. However, the cell-type-specific effects of these variants remain underexplored and are yet to be effectively incorporated into clinical trials. This work leverages single-nucleus RNA sequencing (snRNA-seq) on nuclei from the understudied parietal cortex, enriched in carriers of AD risk-modifying genetic variants, to uncover the cell-type-specific effects these variants exert on neurons and glia. Specifically, this work identified similar, but more extreme gene expression shifts in autosomal dominant AD (ADAD) than in sporadic AD (sAD) compared to controls. It also highlights microglia and oligodendrocyte expression states associated TREM2 variant carriers and an altered activated microglia state associated with a protective variant in the MS4A cluster.Experimental models offer the advantage of controlled environments that allow for the isolation of specific variables, providing clearer insights into the mechanisms underlying AD pathology. Combining these models with human data enhances the translatability of the finding to the human condition. This research also integrates human microglia snRNA-seq data with mouse microglia single-cell RNA sequencing (scRNA-seq) data, demonstrating that microglia from mice with ablated lymphatics cluster more frequently with activated human microglia. This finding underscores the pivotal role of lymphatics in disease outcomes and successful antibody treatments. The study also reveals common Single Nucleotide Polymorphisms (SNPs) in the human population that influence the expression of critical Lymphatic Endothelial Cell (LEC) genes, thereby impacting AD pathology and treatment responses in humans.Understanding Gene Regulatory Networks (GRNs) is crucial for elucidating the complex interactions between genes and their regulatory elements, which ultimately govern cell function and disease progression. This research leverages microglia and astrocyte snRNA-seq data to understand the cell-state-specific GRNs for APOE, revealing a link between APOE expression and the circadian rhythm. This work highlights that a single gene can contribute to different functional systems depending on the cell type, suggesting that therapeutics targeting the expression of specific genes could yield cell-type-specific outcomes.In conclusion, this work highlights the power of snRNA-seq in addressing challenges in the successful development of therapeutic interventions for AD. It emphasizes the importance of uncovering the genetic heterogeneity driving disease subclasses and the need for translating discoveries from mouse model systems to the human condition.  
Subject Added Entry-Topical Term  
Bioinformatics.
Subject Added Entry-Topical Term  
Genetics.
Subject Added Entry-Topical Term  
Neurosciences.
Subject Added Entry-Topical Term  
Public health.
Subject Added Entry-Topical Term  
Pathology.
Index Term-Uncontrolled  
Alzheimer's disease
Index Term-Uncontrolled  
Therapeutics
Index Term-Uncontrolled  
Genome-Wide Association Studies
Index Term-Uncontrolled  
Lymphatic Endothelial Cell genes
Index Term-Uncontrolled  
Genetic heterogeneity
Added Entry-Corporate Name  
Washington University in St. Louis Biology & Biomedical Sciences (Human & Statistical Genetics)
Host Item Entry  
Dissertations Abstracts International. 86-02B.
Electronic Location and Access  
로그인을 한후 보실 수 있는 자료입니다.
Control Number  
joongbu:658161

MARC

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■040    ▼aMiAaPQ▼cMiAaPQ
■0820  ▼a574
■1001  ▼aBrase,  Logan.▼0(orcid)0000-0002-7175-3208
■24510▼aEmploying  Single-Nucleus  RNA-Seq  to  Uncover  Genetic  Factors  of  Alzheimer  Disease.
■260    ▼a[S.l.]▼bWashington  University  in  St.  Louis.  ▼c2024
■260  1▼aAnn  Arbor▼bProQuest  Dissertations  &  Theses▼c2024
■300    ▼a214  p.
■500    ▼aSource:  Dissertations  Abstracts  International,  Volume:  86-02,  Section:  B.
■500    ▼aAdvisor:  Harari,  Oscar;Karch,  Celeste  M.
■5021  ▼aThesis  (Ph.D.)--Washington  University  in  St.  Louis,  2024.
■520    ▼aAlzheimer's  disease  (AD)  stands  as  a  daunting  global  health  challenge,  affecting  millions  of  individuals  worldwide.  This  burden  will  only  intensify  with  an  aging  global  population.  Despite  significant  advances  in  understanding  AD,  further  exploration  is  needed  to  enhance  the  development  of  treatments  and  therapeutics.  Particularly,  I  am  interested  in  identifying  the  molecular  pathways  involved  and  the  cell  types  mediating  the  etiology  of  AD.  This  work  underscores  the  ability  of  single  nucleus  RNA-seq  to  investigate  these  pathways  at  the  cell-type  level  and  mitigate  many  of  the  hurdles  limiting  the  successful  development  of  treatments  for  AD,  including  genetic  heterogeneity  and  translation  of  discoveries  in  model  systems  to  humans.  Through  Genome-Wide  Association  Studies  (GWAS),  numerous  critical  genetic  loci  influencing  disease  risk  and  pathological  development  have  been  identified.  However,  the  cell-type-specific  effects  of  these  variants  remain  underexplored  and  are  yet  to  be  effectively  incorporated  into  clinical  trials.  This  work  leverages  single-nucleus  RNA  sequencing  (snRNA-seq)  on  nuclei  from  the  understudied  parietal  cortex,  enriched  in  carriers  of  AD  risk-modifying  genetic  variants,  to  uncover  the  cell-type-specific  effects  these  variants  exert  on  neurons  and  glia.  Specifically,  this work  identified  similar,  but  more  extreme  gene  expression  shifts  in  autosomal  dominant  AD  (ADAD)  than  in  sporadic  AD  (sAD)  compared  to  controls.  It  also  highlights  microglia  and  oligodendrocyte  expression  states  associated  TREM2  variant  carriers  and  an  altered  activated  microglia  state  associated  with  a  protective  variant  in  the  MS4A  cluster.Experimental  models  offer  the  advantage  of  controlled  environments  that  allow  for  the  isolation  of  specific  variables,  providing  clearer  insights  into  the  mechanisms  underlying  AD  pathology.  Combining  these  models  with  human  data  enhances  the  translatability  of  the  finding  to  the  human  condition.  This  research  also  integrates  human  microglia  snRNA-seq  data  with  mouse  microglia  single-cell  RNA  sequencing  (scRNA-seq)  data,  demonstrating  that  microglia  from  mice  with  ablated  lymphatics  cluster  more  frequently  with  activated  human  microglia.  This  finding  underscores  the  pivotal  role  of  lymphatics  in  disease  outcomes  and  successful  antibody  treatments.  The  study  also  reveals  common  Single  Nucleotide  Polymorphisms  (SNPs)  in  the  human  population  that  influence  the  expression  of  critical  Lymphatic  Endothelial  Cell  (LEC)  genes,  thereby  impacting  AD  pathology  and  treatment  responses  in  humans.Understanding  Gene  Regulatory  Networks  (GRNs)  is  crucial  for  elucidating  the  complex  interactions  between  genes  and  their  regulatory  elements,  which  ultimately  govern  cell  function  and  disease  progression.  This  research  leverages  microglia  and  astrocyte  snRNA-seq  data  to  understand  the  cell-state-specific  GRNs  for  APOE,  revealing  a  link  between  APOE  expression  and  the  circadian  rhythm.  This  work  highlights  that  a  single  gene  can  contribute  to  different  functional  systems  depending  on  the  cell  type,  suggesting  that  therapeutics  targeting  the  expression  of  specific  genes  could  yield  cell-type-specific  outcomes.In  conclusion,  this  work  highlights  the  power  of  snRNA-seq  in  addressing  challenges  in  the  successful  development  of  therapeutic  interventions  for  AD.  It  emphasizes  the  importance  of uncovering  the  genetic  heterogeneity  driving  disease  subclasses  and  the  need  for  translating  discoveries  from  mouse  model  systems  to  the  human  condition.  
■590    ▼aSchool  code:  0252.
■650  4▼aBioinformatics.
■650  4▼aGenetics.
■650  4▼aNeurosciences.
■650  4▼aPublic  health.
■650  4▼aPathology.
■653    ▼aAlzheimer's  disease
■653    ▼aTherapeutics
■653    ▼aGenome-Wide  Association  Studies
■653    ▼aLymphatic  Endothelial  Cell  genes
■653    ▼aGenetic  heterogeneity
■690    ▼a0715
■690    ▼a0369
■690    ▼a0317
■690    ▼a0573
■690    ▼a0571
■71020▼aWashington  University  in  St.  Louis▼bBiology  &  Biomedical  Sciences  (Human  &  Statistical  Genetics).
■7730  ▼tDissertations  Abstracts  International▼g86-02B.
■790    ▼a0252
■791    ▼aPh.D.
■792    ▼a2024
■793    ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17162703▼nKERIS▼z이  자료의  원문은  한국교육학술정보원에서  제공합니다.

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