Investigation of nuclear transport dysfunction in an ocular model of FTLD
Investigation of nuclear transport dysfunction in an ocular model of FTLD
批准号:
8568516
负责人:
Michael Emmerson Ward
金额:
$22.51万
依托单位国家:
美国
项目类别:
财政年份:
2013
资助国家:
美国
项目状态:
已结题
起止时间:
2013-09-01 至 2018-07-31
关键词:
AddressAdvisory CommitteesBasic ScienceBindingBiochemicalBiological AssayBlindnessBrainCell AgingCell DeathCell NucleusCellsCellular biologyCessation of lifeClinicalComplementary DNACytoplasmDNADNA-Binding ProteinsDataDementiaDevelopmentDiseaseDominant-Negative MutationEnvironmentExhibitsEyeFluorescence Resonance Energy TransferFrontotemporal DementiaFunctional disorderGenesGenetic TranscriptionGoalsGrantGuanosine TriphosphateImaging TechniquesImpaired cognitionImpairmentIn VitroIndividualInstitutesInvestigationKnock-outKnockout MiceLasersLeadLocationMediatingMentorsMentorshipMessenger RNAMicroscopyModelingMolecularMolecular Biology TechniquesMonomeric GTP-Binding ProteinsMusMutationNerve DegenerationNeurodegenerative DisordersNeurologyNeuronal DysfunctionNeuronsNuclearNuclear ImportOphthalmologistOphthalmoscopyOrganPathway interactionsPatientsPhenotypeProgranulinRNA ProcessingRNA-Binding ProteinsRecombinantsRecordsReportingResearchResearch PersonnelRetinaRetinalRetinal Ganglion CellsReverse Transcriptase Polymerase Chain ReactionRunningScanningScientistSecondary toSymptomsTestingTrainingTranscription ProcessVisualWorkagedalpha Karyopherinsbasecareercell agecellular imagingfunctional statusgranulinimprovedin vivomouse modelmutantneuronal survivalneuropathologynovelnovel diagnosticsnovel therapeuticsnuclear transport factor 2nucleocytoplasmic transportprogranulin proteinprotein TDP-43protein expressionpublic health relevanceresearch studyretinal nerve fiber layerretinal neuronskillssmall hairpin RNAtherapeutic targettraffickingvisual information
中文摘要
项目总结:痴呆症患者经常抱怨视力障碍,但给予他们的
英文摘要
Project Summary: Patients with dementing illnesses frequently complain of visual dysfunction, but given their
cognitive dysfunction these symptoms may be overlooked. Though the cause of visual loss in dementing
illnesses is poorly understood, it is likely that degeneration of the brain and eye share common molecular
pathways. We discovered that patients with frontotemporal lobar dementia (FTLD), the most common cause of
dementia in patients <60 years old, develop thinning of retinal nerve fiber layer (RNFL), indicating a loss of
retinal ganglion cells (RGCs). We observed a similar phenotype in a mouse model of familial FTLD caused by
loss of expression of the protein progranulin (PGRN). Using this new retinal model of FTLD, we are now able
to probe previously inaccessible questions regarding FTLD pathophysiology.
TDP-43 is a DNA/RNA binding protein that is normally concentrated in the nucleus. In many FTLD patients,
nuclear depletion of TDP43 occurs and this loss contributes to neuron death. We found that RGCs from
PGRN-knockout (KO) mice also exhibited nuclear depletion of TDP43. These cells also had impaired nuclear
import of TDP43, and further study revealed that PGRN-KO RGCs with nuclear depletion of TDP43 also had
loss of expression of the small GTPase Ran, a master regulator of nuclear transport.
This proposal explores how loss of PGRN results in impaired Ran function, and how dysfunctional Ran-
mediated nuclear transport leads to TDP43 mislocalization and RGC death. In Aim 1, I will use microscopy and
molecular biology techniques to determine how PGRN loss disrupts Ran-mediated nuclear trafficking in RGCs.
In Aim 2, I will use classic in vitro nuclear transport assays, expression approaches in primary RGCs, and in
vivo rescue experiments to determine how abnormal Ran-mediated nuclear trafficking leads to TDP43
mislocalization and RGD death. A better understanding of these phenomena is a necessary first step in my
long-term goal of developing novel therapies for patients with vision loss or dementia. I have a strong
background in neurology and basic research and am thus well poised to carry out this project. The proposed
training will take place jointly at the Gladstone Institutes and UCSF, both of which have long track records of
training independent clinical-scientists. My primary mentor, Dr. Li Gan, is an expert at modeling
neurodegenerative conditions in mice, and my co-mentor, Dr. Ari Green, is adept in retinal imaging techniques.
I will augment their mentorship with an interdisciplinary advisory committee made up of a senior
ophthalmologist (Dr. Stephen McLeod), experts in RGC biology and death (Drs. Erik Ullian and David
Sretavan), an expert in the biochemical and molecular mechanisms of FTLD (Dr. Bob Farese), and a FTLD
neuropathology expert (Dr. Bill Seeley). The skills gained through conducting the proposed studies in a
mentored environment, combined with relevant coursework, professional development opportunities, and
judicious subspecialty clinical training, will prepare me to launch my career as an independent investigator.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Investigation of nuclear transport dysfunction in an ocular model of FTLD
-
批准号:8728869
-
项目类别:
-
资助金额:$22.51万
-
财政年份:2013
-
负责人:Michael Emmerson Ward
-
依托单位:
海外基金