Administrative Supplement: Neurobiological role of MicroRNA in Alzheimer's

行政补充：MicroRNA 在阿尔茨海默病中的神经生物学作用

• 批准号: 9321507
• 负责人: DEBOMOY K LAHIRI
• 金额: $ 15.58万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9321507
• 关键词: Abeta synthesis; Address; Administrative Supplement; Affect; Alzheimer' s Disease; Amyloid; Amyloid Proteins; Amyloid beta-Protein; Animal Model; Biological; Brain; Cells; Clinical Trials; Dementia; Deposition; Disease; Disease Progression; Drug Targeting; Elderly; Elements; Enzymes; Etiology; Failure; Gene Expression Regulation; Genes; Goals; Health; Homeostasis; Human; Impaired cognition; Iron; Iron Regulatory Protein 1; Lead; Link; Mediating; Messenger RNA; MicroRNAs; Molecular; Nerve Degeneration; Neurobiology; Neurodegenerative Disorders; Pathology; Pathway interactions; Patients; Pattern; Peptides; Phase; Physiological; Play; Post-Transcriptional Regulation; Process; Production; Property; Protein Precursors; Proteins; RNA Interference; Regulation; Regulatory Pathway; Research; Rodent; Rodent Model; Role; Sampling; Site; Specificity; Symptoms; Testing; Therapeutic Agents; Transcript; Transgenic Animals; Transgenic Mice; Translations; Untranslated RNA; Untranslated Regions; Work; base; beta secretase; beta-site APP cleaving enzyme 1; cell type; cohort; disorder control; fetal; gene correction; gene product; improved; in vivo; member; mimicry; mouse model; new therapeutic target; novel; novel strategies; novel therapeutic intervention; novel therapeutics; protein expression; secretase; therapeutic target; transcriptome

 DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common cause of dementia in the elderly. Because current treatments provide modest symptomatic relief and do not slow AD progression, a better understanding of molecular bases of AD pathology is needed. This proposal will identify and validate microRNAs (miRNAs) as a new class of drug targets. miRNAs are endogenous, short, non-coding RNAs that typically inhibit protein expression by interacting with specific recognition elements of target transcripts. AD is believed to result from overproduction of amyloid-ß peptide (Aß), derived from Aß precursor protein (APP), and dysregulation of proteins involved in Aß production (e.g. APP, ß-secretase/BACE1) contributes to excess Aß deposition. We have also recently found that miRNA can stimulate APP expression in interaction with iron homeostasis. We propose to study APP and BACE1 regulation by miRNA. We hypothesize specific miRNAs regulate endogenous levels of APP and BACE1, are dysfunctional in AD, and manipulation will reduce Aß. Specific Aim 1(SA1) will identify functional miRNA target sites in APP and BACE1 and validate miRNA post-transcriptional regulation of native APP and BACE1 expression. Rationale: Discover functional miRNA targets in UTRs of APP and BACE1 transcripts using. Endpoints are APP and BACE1 mRNA & proteins, and Aß peptides, which we predict to change with miRNA. Impact: Manipulation of miRNA regulation is a novel therapeutic approach and may be feasible for correcting gene dysregulation in AD. SA2 will test physiological interactions between miRNA validated in SA1 and their regulatory networks over APP and BACE1 expression. Rationale: Test other mechanisms of regulation likely linked to maintain homeostasis of APP, BACE1 and Aß. Identifying roles of miRNA in this network is vital to pharmacologically target miRNA-transcript interactions. Impact: Reveal novel mechanisms for miRNA function in AD. SA3 will assess effects of in vivo manipulation of validated miRNA in AD animal models. Rationale: Test our validated miRNAs as therapeutic targets in AD transgenic animals, including interaction with iron homeostasis, by inducing miRNA-dependent changes in translation. Impact: Validate specific miRNAs as drug targets in vivo and identify novel AD-related regulatory networks. SA4 will examine whether miRNAs implicated in regulatory control of gene products involved in Aß homeostasis are dysregulated in AD patients. Rationale: In SA1-3, we will identify pertinent miRNAs that modulate expression of gene products implicated in Aß production. If these miRNAs are also involved in AD pathology, we expect their regulation to vary in anatomical- and pathology-dependent patterns. Impact: Further demonstrate validity of miRNAs as therapeutic targets to treat AD-related dysregulation. Research dictated by our central hypothesis could cause a significant paradigm shift on the field by elucidating novel regulatory mechanisms and identifying specific miRNAs that regulate important gene products implicated in AD. Final impact will be in eventual use of these new drug targets to produce therapeutic agents to slow or halt progression in AD.