Mitochondrial Genomics and Peripheral Neuropathy during HIV Therapy

HIV 治疗期间的线粒体基因组学和周围神经病变

• 批准号: 7383762
• 负责人: TODD M HULGAN
• 金额: $ 15.35万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-15 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7383762
• 关键词: AIDS clinical trial group; Acquired Immunodeficiency Syndrome; Address; Area; Arts; Biological Markers; Biological Models; Biology; Biomedical Research; Blood; Class; Clinical Research; Clinical Trials; Cohort Studies; Complication; Computing Methodologies; Condition; DNA; DNA Sequence; Data; Development; Diagnosis; Discipline; Disease; Drug toxicity; Epidemic; Epidemiology; Ethnic group; Exposure to; Frequencies; Future; Genetic; Genetic Polymorphism; Genomics; HIV; HIV-1; Human; Individual; Infection; Injury; Institutes; Knowledge; Length; Life; Medicine; Mission; Mitochondria; Mitochondrial DNA; Morbidity - disease rate; Nerve; Nerve Fibers; Nested Case-Control Study; Neurologic; Neurons; Nucleosides; Numbers; Outcome; Participant; Pathogenesis; Patients; Pattern; Peripheral Nervous System Diseases; Persons; Play; Ploidies; Population; Predisposition; Prevention; Protocols documentation; Reporting; Research; Resources; Reverse Transcriptase Inhibitors; Risk Factors; Role; Serum; Severities; Single Nucleotide Polymorphism; Specimen; Stroke; Technology; Testing; Tissues; Toxic effect; Translating; Treatment Protocols; Variant; Work; antiretroviral therapy; base; clinically relevant; cohort; density; genome sequencing; genotyping technology; high throughput technology; human disease; improved; knowledge base; mitochondrial genome; mortality; nervous system disorder; novel; peripheral blood; prevent; programs; prospective; racial and ethnic; repository; tool; treatment trial; volunteer

DESCRIPTION (provided by applicant): Potent antiretroviral therapy (ART) including nucleoside reverse transcriptase inhibitors (NRTI) substantially reduces morbidity and mortality due to human immunodeficiency virus type 1 (HIV) infection and acquired immunodeficiency syndrome (AIDS), but is frequently limited by mitochondrial toxicity. Peripheral neuropathy (PN) is a common, debilitating toxicity that is often irreversible. Variation in the onset, character, and severity of NRTI-associated PN strongly suggests host genetics play a role, but an understanding of this role has been elusive. As life-saving ART becomes increasingly available in resource-limited settings, we can anticipate a future "epidemic" of PN in new populations unless improved understanding and technology can be rapidly translated to these settings. The overarching hypothesis of this proposal is that improved understanding of associations between variation in the human mitochondrial genome and ART-induced PN through the application of state-of-the-art technology (high- throughput whole mitochondrial genome sequencing) and computational resources (to include multifactor dimensionality reduction) can prevent this toxicity and ultimately improve long-term ART outcomes. The proposed work will expand on the existing base of knowledge regarding mitochondrial effects of ART, and will explore novel areas by addressing two specific aims: 1) To characterize mitochondrial DNA (mtDNA) polymorphisms, including multilocus genetic interactions, that confer increased susceptibility to the development of symptomatic PN among HIV-infected individuals treated with NRTI-containing ART regimens; and 2) To characterize relationships between mtDNA polymorphisms and markers of neuronal and mitochondrial injury, including epidermal nerve fiber densities, serum lactate concentrations, and peripheral blood mtDNA content. We propose to address these aims through nested case-control studies using stored DNA and available data from 800 HIV-infected clinical study participants. Information from these studies will allow clinicians to better individualize HIV therapy, avoiding debilitating, often irreversible, and costly complications, thus having important applications in both affluent and resource-limited parts of the world. Results from this study will also advance the field of "mitochondrial medicine", having broad application across other scientific disciplines and for other human diseases.

描述（由申请人提供）：包括核苷逆转录酶抑制剂（NRTI）在内的有效抗逆转录病毒疗法（ART）可显着降低1型人类免疫缺陷病毒（HIV）感染和获得性免疫缺陷综合症（AIDS）引起的发病率和死亡率，但常常受到以下因素的限制：线粒体毒性。周围神经病变 (PN) 是一种常见的、使人衰弱的毒性，通常是不可逆转的。 NRTI 相关 PN 的发病、特征和严重程度的变化强烈表明宿主遗传学发挥了作用，但对该作用的理解一直难以捉摸。随着挽救生命的 ART 在资源有限的环境中变得越来越可用，我们可以预见未来 PN 在新人群中的“流行”，除非更好的理解和技术可以迅速转化为这些环境。该提案的总体假设是，通过应用最先进的技术（高通量全线粒体基因组测序）和计算资源（以包括多因素降维）可以预防这种毒性并最终改善长期 ART 结局。拟议的工作将扩展有关 ART 线粒体影响的现有知识基础，并将通过解决两个具体目标来探索新领域：1）表征线粒体 DNA (mtDNA) 多态性，包括多位点遗传相互作用，这些多态性可增加对 ART 的易感性。在接受含 NRTI 的 ART 方案治疗的 HIV 感染者中出现症状性 PN； 2) 表征 mtDNA 多态性与神经元和线粒体损伤标志物之间的关系，包括表皮神经纤维密度、血清乳酸浓度和外周血 mtDNA 含量。我们建议通过巢式病例对照研究来实现这些目标，该研究使用存储的 DNA 和 800 名 HIV 感染者临床研究参与者的可用数据。这些研究的信息将使临床医生能够更好地个体化艾滋病毒治疗，避免使人衰弱、往往不可逆转且代价高昂的并发症，从而在世界富裕和资源有限的地区都有重要的应用。这项研究的结果也将推动“线粒体医学”领域的发展，在其他科学学科和其他人类疾病中具有广泛的应用。