Investigating the role of neuronal SYNJ2 in mRNA transport and mitochondrial function
研究神经元 SYNJ2 在 mRNA 转运和线粒体功能中的作用
基本信息
- 批准号:10747226
- 负责人:
- 金额:$ 5.2万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-01-01 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:Advisory CommitteesAlzheimer&aposs DiseaseAxonBackCell Differentiation processCellsComplexDendritesDiseaseDistalDistantEnsureGoalsHalf-LifeHealthHeterogeneityHomeostasisHumanHuntington DiseaseLaboratoriesMaintenanceMediatingMembraneMentorsMessenger RNAMitochondriaMitochondrial ProteinsModelingMusMutateNerve DegenerationNeuronsPINK1 geneParkinson DiseasePathologicPeripheralPhasePhosphotransferasesPhysiologicalPlayProcessProtein BiosynthesisProteinsRNA BindingRNA Recognition MotifResearchRoleSYNJ1 geneSurfaceTrainingTranscriptTranslationsTravelWorkaxon regenerationaxonal degenerationcareerdiversity and inclusionin vivo regenerationinnovationmetermitochondrial messenger RNAneuronal cell bodyneurotransmissionpreservation
项目摘要
Project Summary
Neurons critically depend on mitochondria function to maintain membrane excitability and execute complex
functions, such as neurotransmission and plasticity. Neurons are highly differentiated cells that require large
amounts of ATP to perform these functions and ensure long-term viability. The unique complexity of neurons is
reflected by the extremely long segments that can extend up to a meter long and the functional heterogeneity
for each neuronal compartment. The neuron has specialized mechanisms to transport mitochondria to the
most distal parts to maintain proper neuronal function and survival. In turn, peripheral mitochondria rely on the
transport of cellular components, such as mRNA and proteins, to sustain mitochondrial homeostasis without
the need to travel back to the soma. The current proposal focuses on this aspect of mitochondrial
maintenance, mitochondrial transcripts' ability to be trafficked to the axons for local translation, and how this
influences mitochondrial and neuronal health and function.
This project's significance is focused on PINK1, an essential mitochondrial kinase that is mutated in a
hereditable form of Parkinson's disease. PINK1 protein will not survive transport down the axon because of its
short half-life. To this end, our laboratory described an innovative mechanism by which mitochondria carry
PINK1 mRNA on its surface to axons. Synaptojanin 2 (SYNJ2) was found to be responsible for tethering
PINK1 mRNA to the mitochondria for axonal localization and local protein synthesis. The study of this
neuronal-specific model suggests that the RNA binding function of SYNJ2 is required for PINK1-mediated
processes (such as mitophagy); however, this has yet to be explored. The work planned in this proposal will
explore the physiological and pathological consequence of disrupting the RNA binding function of SYNJ2,
and; this unique approach is of critical importance for understanding mitochondrial mRNA transport and
translation for preserving mitochondrial health.
Thus, I hypothesize that Hypothesis: The RNA Recognition Motif of SYNJ2 causes PINK1 mRNA to
colocalize with and be transported with mitochondria in a manner critical for PINK1 functions in axons
and dendrites and thereby for maintaining neuronal health. I have assembled an advisory committee to
provide conceptual and technical guidance as I explore the following Specific Aims: Aim 1: Examine the
function of endogenous SYNJ2 and its RNA recognition motif in mice. Aim 2: Establish the role of peripheral
SYNJ2 in mediating axonal mitochondrial function and neuronal health Aim 3: Investigate the impact of SYNJ2
RNA binding function in modulating axonal degeneration and regeneration in vivo. I have also developed a
tailored diversity and inclusion training plan to execute during the mentored phase. The proposed studies and
mentoring plans described in this proposal will provide me with a robust training platform to launch my
independent academic research career.
Project Summary
Neurons critically depend on mitochondria function to maintain membrane excitability and execute complex
functions, such as neurotransmission and plasticity. Neurons are highly differentiated cells that require large
amounts of ATP to perform these functions and ensure long-term viability. The unique complexity of neurons is
reflected by the extremely long segments that can extend up to a meter long and the functional heterogeneity
for each neuronal compartment. The neuron has specialized mechanisms to transport mitochondria to the
most distal parts to maintain proper neuronal function and survival. In turn, peripheral mitochondria rely on the
transport of cellular components, such as mRNA and proteins, to sustain mitochondrial homeostasis without
the need to travel back to the soma. The current proposal focuses on this aspect of mitochondrial
maintenance, mitochondrial transcripts' ability to be trafficked to the axons for local translation, and how this
influences mitochondrial and neuronal health and function.
This project's significance is focused on PINK1, an essential mitochondrial kinase that is mutated in a
hereditable form of Parkinson's disease. PINK1 protein will not survive transport down the axon because of its
short half-life. To this end, our laboratory described an innovative mechanism by which mitochondria carry
PINK1 mRNA on its surface to axons. Synaptojanin 2 (SYNJ2) was found to be responsible for tethering
PINK1 mRNA to the mitochondria for axonal localization and local protein synthesis. The study of this
neuronal-specific model suggests that the RNA binding function of SYNJ2 is required for PINK1-mediated
processes (such as mitophagy); however, this has yet to be explored. The work planned in this proposal will
explore the physiological and pathological consequence of disrupting the RNA binding function of SYNJ2,
and; this unique approach is of critical importance for understanding mitochondrial mRNA transport and
translation for preserving mitochondrial health.
Thus, I hypothesize that Hypothesis: The RNA Recognition Motif of SYNJ2 causes PINK1 mRNA to
colocalize with and be transported with mitochondria in a manner critical for PINK1 functions in axons
and dendrites and thereby for maintaining neuronal health. I have assembled an advisory committee to
provide conceptual and technical guidance as I explore the following Specific Aims: Aim 1: Examine the
function of endogenous SYNJ2 and its RNA recognition motif in mice. Aim 2: Establish the role of peripheral
SYNJ2 in mediating axonal mitochondrial function and neuronal health Aim 3: Investigate the impact of SYNJ2
RNA binding function in modulating axonal degeneration and regeneration in vivo. I have also developed a
tailored diversity and inclusion training plan to execute during the mentored phase. The proposed studies and
mentoring plans described in this proposal will provide me with a robust training platform to launch my
independent academic research career.
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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Whitney Sharee Gibbs其他文献
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{{ truncateString('Whitney Sharee Gibbs', 18)}}的其他基金
Investigating the role of neuronal SYNJ2 in mRNA transport and mitochondrial function
研究神经元 SYNJ2 在 mRNA 转运和线粒体功能中的作用
- 批准号:
10429567 - 财政年份:2022
- 资助金额:
$ 5.2万 - 项目类别:
Investigating the Role of Neuronal SYNJ2 in mRNA Transport and Mitochondrial Function
研究神经元 SYNJ2 在 mRNA 运输和线粒体功能中的作用
- 批准号:
10596171 - 财政年份:2022
- 资助金额:
$ 5.2万 - 项目类别: