Research Component 4

研究部分 4

• 批准号: 8374135
• 负责人: PING ZHANG
• 金额: $ 10.46万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8374135
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adverse effects; Affect; Agranulocytosis; Alcohol abuse; Alcohol consumption; Alcohols; Attenuated; Blood Circulation; Bone Marrow; Bone Marrow Examination; CD4 Positive T Lymphocytes; Cell Count; Cell physiology; Complex; CpG Islands; Data; Development; Disease; Dysmyelopoietic Syndromes; Environment; Equilibrium; Foundations; HIV; Hematopoietic; Hematopoietic stem cells; Highly Active Antiretroviral Therapy; Histone Acetylation; Host Defense; Immunologic Deficiency Syndromes; Individual; Infiltration; Instruction; Investigation; Knowledge; Lymphocyte; Macaca; Macaca mulatta; Mediating; Mesenchymal; Methylation; Myelogenous; Myelopoiesis; Myelosuppression; Patients; Research; Risk Factors; SIV; Sampling; Stromal Cells; Testing; Transforming Growth Factors; Virus Diseases; Virus Replication; alcohol effect; alcohol exposure; antiretroviral therapy; effective therapy; granulocyte; improved; injured; mortality; novel; precursor cell; progenitor; promoter; protective effect; research study; response; secondary infection; stem cell differentiation; transcription factor

Myelosuppression with granulocytopenia is a common hematologic disorder during HIV infection. Compounding the direct lymphotoxicity of HIV. granulocytopenia is an additional risk factor for secondary infections. Management of granulocytopenia improves survival of patients with HIV infection. Alcohol abuse is a significant co-factor for progression of AIDS. Alcohol injures the bone marrow and impairs myelopoiesis. Antiretroviral therapy (ART) suppresses HIV/SIV replication and has also been shown to ameliorate HIVassociated granulocytopenia. However. ART itself can be myelotoxic. The effects of alcohol on myelosuppression associated with HIV infection and on the protection of ART against granulocytopenia developed during HIV infection are unknown. Our preliminary studies show that SIV infection caused a decrease in granulocyte counts in association with the reduction of CD4+ cell numbers in the circulation. Alcohol consumption aggravated the myelosuppression during SIV infection and exaggerated ART-induced myelotoxicity. Further, alcohol inhibited myelopoietic transcription factor expression by hematopoietic precursors and perturbed the bone marrow environment, inducing a myeloid differentiation block. In this project, we propose to investigate the mechanisms by which alcohol adversely affects hematopoietic stem cell commitment to myeloid lineage development during SIV infection. The experimental focus of this proposal is that alcohol exaggerates myelosuppression during SIV infection and counteracts the protective effects of ART on myelopoiesis. The three Specific Aims are: 1). to test the hypothesis that alcohol suppresses hematopoietic stem cell commitment to granulocyte lineage development during SIV infection; 2). to test the hypothesis that alcohol impairs myeloid differentiation during SIV infection by disrupting the hematopoietic microenvironment; 3: to test the hypothesis that alcohol exaggerates the myelotoxicity of ART. Novel information obtained from this investigation will greatly advance our knowledge concerning the negative impact of alcohol abuse on myelopoiesis in HIV-infected patients. It will also form a foundation for developing effective therapies to treat the combined immunodeficiencies in HIV-infected alcohol abusers.

粒细胞减少症的骨髓抑制是HIV感染期间常见的血液学疾病。使HIV的直接淋巴毒性复合。粒细胞减少是继发感染的额外危险因素。粒细胞减少症的治疗可改善HIV感染患者的存活率。酗酒是艾滋病进展的重要联合因素。酒精会损伤骨髓并损害骨髓病。抗逆转录病毒疗法（ART）抑制了HIV/SIV复制，并且还显示出可以改善Hivassy Cossiped hivassiped粒细胞减少症。然而。艺术本身可以是骨髓毒性的。酒精对与HIV感染相关的骨髓抑制以及在HIV感染期间发育的粒细胞减少症相关的骨髓抑制的影响尚不清楚。我们的初步研究表明，SIV感染与循环中CD4+细胞数量的减少有关，导致粒细胞计数降低。饮酒在SIV感染期间加剧了骨髓抑制，并夸大了艺术引起的骨髓毒性。此外，酒精通过造血前体抑制骨髓转录因子的表达，并扰动骨髓环境，诱导髓样分化阻滞。在该项目中，我们建议研究酒精对SIV感染期间粒细胞谱系发育的造血干细胞承诺的不利影响的机制。该提议的实验重点是，酒精在SIV感染过程中夸大了骨髓抑制，并抵消了艺术对骨髓造成的保护作用。三个特定目标是：1）。为了测试酒精抑制造血干细胞对SIV感染期间粒细胞谱系发育的承诺的假设； 2）。为了检验以下假设，即酒精通过破坏造血微环境而损害SIV感染过程中的髓样分化； 3：测试酒精夸大艺术的骨髓毒性的假设。从这项研究中获得的新信息将大大提高我们关于酗酒对HIV感染患者的骨髓病的负面影响的知识。它还将构成开发有效疗法的基础，以治疗艾滋病毒感染的酗酒者的合并免疫缺陷。