Altering Energy Balance by Systemic Delivery of RNAi to the Neuroendocrine Brain
Altering Energy Balance by Systemic Delivery of RNAi to the Neuroendocrine Brain
批准号:
8539523
负责人:
Sergio R Ojeda
金额:
$20.04万
依托单位国家:
美国
项目类别:
财政年份:
2012
资助国家:
美国
项目状态:
已结题
起止时间:
2012-09-01 至 2014-08-31
关键词:
AccountingAdrenal GlandsAdultAffectAnimal ModelAnimalsBasic ScienceBindingBody CompositionBody WeightBrainBrain StemCapsidCellsChildhoodDependovirusDevelopmentDiseaseEatingEnergy MetabolismEngineeringEpitopesFeeding behaviorsGene ExpressionGenesGoalsHealthHome environmentHomeostasisHumanHypothalamic DiseasesHypothalamic structureInjection of therapeutic agentKnockout MiceLibrariesLifeMeasuresMethodsMicroRNAsMicroinjectionsNeuroendocrine CellNeuronsNeurosecretory SystemsNutritionalObesityPeptidesPeripheralPhage DisplayPituitary GlandPlayPopulationPregnancyPro-OpiomelanocortinProceduresRNA InterferenceRattusReadingRegulationRelative (related person)RodentRoleSiteSpecificityStructureStructure of nucleus infundibularis hypothalamiSystemTechniquesTechnologyTestingTherapeutic InterventionTransgenic OrganismsTropismViralVirusadeno-associated viral vectorbaseblood glucose regulationcell typecellular transductioncritical developmental periodenergy balanceheparin proteoglycanin vivointerestknock-downminimally invasiveneuropeptide Ynovelnovel strategiesoverexpressionparticlepostnatalprogramsprototypereceptortool
中文摘要
描述(由申请人提供):迄今为止,操纵下丘脑功能主要依赖于使用条件性敲除小鼠或转基因过表达。这些方法的主要局限性在于,它们没有考虑到神经内分泌神经元及其投射发育的复杂性,以及当这些神经元在生命早期被操纵时发生的补偿性适应。或者,显微注射腺相关病毒(AAV)递送siRNA已被用于修改成年下丘脑功能。这种技术的最大局限性是侵入性和相对低效率的程序。本申请旨在通过开发一种新颖的微创方法来以时间上限定的和细胞特异性的方式操纵下丘脑神经元功能来规避这些限制。在可用作这些研究原型的下丘脑系统中,弓状核(ARC)的黑皮质素系统是一个理想的候选者。它已被广泛研究,并显示通过调节食物摄入、体重和葡萄糖稳态在调节能量平衡中发挥关键作用。它由两个主要的神经元群体组成,具有相反的功能;含有前阿黑皮素(POMC)的神经元抑制进食的冲动并刺激能量消耗,含有神经肽Y/Agouti相关肽(NPY/AgRP)的神经元刺激进食行为并抑制能量消耗。通过测量食物摄入量和体重,可以可靠地非侵入性地评估改变任一神经元子集的功能的后果。从人类健康的角度来看,开发新的工具来研究这一系统具有巨大的价值;由于早期生活中营养改变导致儿童和成人肥胖的急剧增加,迫切需要开发新的方法来更好地了解控制进食行为和能量稳态的中枢机制。这是一个特别重要的问题,因为能量平衡可能会受到“发育规划”关键时期营养挑战的永久影响,人类的“发育规划”发生在妊娠后期,啮齿动物发生在出生后早期。我们建议开发的技术的一个主要优点是,它可以用来修改ARC功能后,能量平衡的开发编程完成。我们建议通过血管内施用经改造的AAV 2颗粒来将RNA干扰(RNAi)递送至ARC以沉默POMC和AgRP基因。我们预计,这些研究的成功实施将为最终应用类似方法治疗神经内分泌脑疾病铺平道路。我们还预计,这些研究将为基础研究目的和新兴疗法提供新的大脑递送策略的基础。
英文摘要
DESCRIPTION (provided by applicant): To date, manipulating hypothalamic function mostly relies on the use of conditional knockout mice or transgenic overexpression. The major limitation to these approaches is that they do not take into account the complexities in the development of neuroendocrine neurons and their projections, and the compensatory adaptations that occur when these neurons are manipulated during early life. Alternatively, microinjections of adeno-associated viruses (AAV) delivering siRNAs have been used to modify hypothalamic function in adulthood. The greatest limitation of this technique is the invasiveness and relative inefficiency of the procedure. The present application intends to circumvent these limitations by developing a novel, minimally invasive method to manipulate hypothalamic neuronal function in a temporally defined and cell-specific manner. Among the hypothalamic systems that can be used as a prototype for these studies, the melanocortin system of the arcuate nucleus (ARC) stands out as an ideal candidate. It has been extensively studied and shown to play a critical role in regulating energy balance through modulation of food intake, body weight and glucose homeostasis. It is composed of two major populations of neurons with opposite functions; neurons containing pro-opiomelanocortin (POMC) inhibit the drive to eat and stimulate energy expenditure, neurons containing neuropeptide Y/Agouti-related peptide (NPY/AgRP) stimulate feeding behavior and inhibit energy expenditure. The consequences of altering the functions of either neuronal subset can be reliably assessed non-invasively, by measuring food intake and body weight. From the human health standpoint, developing new tools to study this system has an enormous value; the dramatic increase in childhood and adult obesity resulting from nutritional alterations during early life makes it urgent to develop novel methods to better understand the central mechanisms underlying the control of feeding behavior and energy homeostasis. This is a particularly important issue because energy balance can be permanently affected by nutritional challenges taking place during the critical period of "developmental programming" that in humans occurs during late gestation and in rodents, during the early postnatal period. A major advantage of the technology we propose to develop is that it can be used to modify ARC function after the developmental programming of energy balance is complete. We propose to silence the POMC and AgRP genes by delivering RNA interference (RNAi) to the ARC via the intravascular administration of modified AAV2 particles engineered to transduce hypothalamic cells. We anticipate that the successful execution of these studies will pave the way to the eventual application of similar approaches to treat disorders of the neuroendocrine brain. We also anticipate that these studies will provide the basis for new delivery strategies to the brain for basic research purposes and emerging therapies.
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会议论文
Altering Energy Balance by Systemic Delivery of RNAi to the Neuroendocrine Brain
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批准号:8427058
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项目类别:
-
资助金额:$26.73万
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财政年份:2012
-
负责人:Sergio R Ojeda
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依托单位:
NEUROENDOCRINE CONTROL OF OVARIAN DEVELOPMENT
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批准号:8357724
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项目类别:
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资助金额:$5.82万
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财政年份:2011
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负责人:Sergio R Ojeda
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依托单位:
NOVEL MECHANISMS UNDERLYING THE TRANSSYNAPTIC CONTROL OF LHRH RELEASE
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批准号:8357725
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项目类别:
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资助金额:$3.63万
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财政年份:2011
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负责人:Sergio R Ojeda
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依托单位:
NEURAL CONTROL OF THE PREPUBERTAL OVARY
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批准号:8357880
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项目类别:
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资助金额:$4.36万
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财政年份:2011
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负责人:Sergio R Ojeda
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依托单位:
NEUROENDOCRINOLOGY OF PUBERTY AND SEXUAL DEVELOPMENT
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批准号:8357881
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项目类别:
-
资助金额:$5.82万
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财政年份:2011
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负责人:Sergio R Ojeda
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依托单位:
NEUROENDOCRINE CONTROL OF FEMALE PUBERTY
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批准号:8357726
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项目类别:
-
资助金额:$5.82万
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财政年份:2011
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负责人:Sergio R Ojeda
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依托单位:
MOLECULAR AND STRUCTURAL BASES OF HYPOTHALAMIC PUBERTY
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批准号:8357754
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项目类别:
-
资助金额:$3.63万
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财政年份:2011
-
负责人:Sergio R Ojeda
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依托单位:
RNA INTERFERENCE THERAPY FOR HUNTINGTON'S DISEASE: STUDIES IN NON-HUMAN PRIMATES
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批准号:8357819
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项目类别:
-
资助金额:$5.82万
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财政年份:2011
-
负责人:Sergio R Ojeda
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依托单位:
INTRODUCING STABLE INFERTILITY BY RNA INTERFERENCE
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批准号:8357818
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项目类别:
-
资助金额:$4.36万
-
财政年份:2011
-
负责人:Sergio R Ojeda
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依托单位:
NEUROENDOCRINE CONTROL OF OVARIAN DEVELOPMENT
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批准号:8173170
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项目类别:
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资助金额:$7.61万
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财政年份:2010
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负责人:Sergio R Ojeda
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依托单位:
SINGLE NUCLEOTIDE GENE POLYMORPHISMS AND FUNCTIONAL HYPOTHALAMIC AMENORRHEA
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批准号:8173254
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项目类别:
-
资助金额:$4.76万
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财政年份:2010
-
负责人:Sergio R Ojeda
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依托单位:
RNA INTERFERENCE THERAPY FOR HUNTINGTON'S DISEASE: STUDIES IN NON-HUMAN PRIMATES
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批准号:8173312
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项目类别:
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资助金额:$7.61万
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财政年份:2010
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负责人:Sergio R Ojeda
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依托单位:
CONTRIBUTION OF FXYD1 TO THE NEUROPATHOLOGY OF RETT SYNDROME
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批准号:8173224
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项目类别:
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资助金额:$4.76万
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财政年份:2010
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负责人:Sergio R Ojeda
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依托单位:
MOLECULAR AND STRUCTURAL BASES OF HYPOTHALAMIC PUBERTY
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批准号:8173211
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项目类别:
-
资助金额:$4.76万
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财政年份:2010
-
负责人:Sergio R Ojeda
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依托单位:
NEUROENDOCRINE CONTROL OF FEMALE PUBERTY
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批准号:8173172
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项目类别:
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资助金额:$7.61万
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财政年份:2010
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负责人:Sergio R Ojeda
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依托单位:
Neural Control of the Prepubertal Ovary
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批准号:8066256
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项目类别:
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资助金额:$7.88万
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财政年份:2010
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负责人:Sergio R Ojeda
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依托单位:
Neuroendocrinology of Puberty and Sexual Development
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批准号:8094789
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项目类别:
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资助金额:$19.8万
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财政年份:2010
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负责人:Sergio R Ojeda
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依托单位:
NOVEL MECHANISMS UNDERLYING THE TRANSSYNAPTIC CONTROL OF LHRH RELEASE
-
批准号:8125590
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项目类别:
-
资助金额:$7.56万
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财政年份:2010
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负责人:Sergio R Ojeda
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依托单位:
INTRODUCING STABLE INFERTILITY BY RNA INTERFERENCE
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批准号:8173311
-
项目类别:
-
资助金额:$5.71万
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财政年份:2010
-
负责人:Sergio R Ojeda
-
依托单位:
NOVEL MECHANISMS UNDERLYING THE TRANSSYNAPTIC CONTROL OF LHRH RELEASE
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批准号:8173171
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项目类别:
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资助金额:$4.76万
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财政年份:2010
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负责人:Sergio R Ojeda
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依托单位:
海外基金