Therapeutic Targets in Acute Chest Syndrome

急性胸部综合症的治疗目标

• 批准号: 10565873
• 负责人: Solomon Fiifi Ofori-Acquah
• 金额: $ 68.95万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-07 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10565873
• 关键词: Acute; Acute Lung Injury; Adult; Africa; African; Age; Azacitidine; Biological; Blood; Blood Cells; Blood Circulation; Cells; Cessation of life; Child; Clinical; Complication; CpG Islands; DNA Methylation; DNA Sequence; Data; Dose; Enrollment; Enzymes; Epigenetic Process; Genes; Genetic; Genetic Diseases; Genomics; Ghana; HL60; Health; Heme; Hemolysis; Human; Individual; Inflammatory; Infusion procedures; Iron; Knock-out; Liver; Longitudinal cohort; Lung; Measures; Messenger RNA; Methylation; MicroRNAs; Modeling; Molecular; Mus; Organ; Outcome; Pathogenesis; Patients; Peripheral Blood Mononuclear Cell; Pilot Projects; Plasma; Population; Pre-Clinical Model; Pregnant Women; Process; Production; Proteins; Recombinants; Reporting; Research; Respiratory distress; Risk; Role; Sampling; Sickle Cell Anemia; Signal Transduction; Site; Stress; Survival Rate; TLR4 gene; Testing; Therapeutic; Time; Toxic effect; Transgenic Mice; Transgenic Organisms; Variant; acute chest syndrome; cohort; conditional knockout; demethylation; design; efficacy testing; enzyme activity; experience; experimental study; extracellular; functional genomics; genome sequencing; genome-wide; heme oxygenase-1; improved; knock-down; mRNA Expression; next generation; next generation sequencing; novel; overexpression; premature; prevent; promoter; prophylactic; targeted treatment; therapeutic target; whole genome

SUMMARY This project is aimed at improving the health of individuals who have sickle cell disease (SCD) by defining a potential pro-survival factor of acute chest syndrome (ACS), and exploring whether this factor can be developed as a molecular therapeutic. ACS is the leading pulmonary complication and a common cause of premature death in SCD. There is no specific treatment for ACS despite decades of intensive research, and so it continues to be a major clinical problem in SCD, particularly, in Africa. We recently discovered that extracellular heme triggers ACS in an inflammatory process involving toll-like receptor 4 signaling. A growing number of experimental, clinical and genomics studies support this model of ACS pathogenesis in which extracellular heme triggers the acute lung injury. In this new R01 project, we test the novel idea that children express supra-physiological levels of heme oxygenase-1 (HO-1), the rate-limiting heme degradation enzyme. We posit that the high-level HO-1 in children enhances their ability to clear excess heme from the blood circulation to improve their overall outcome from ACS. In pilot studies, we found that replenishing HO-1 in the plasma of adult SCD mice improved ACS survival. These prior research provide a strong rationale to understand how endogenous HO-1 production is regulated in SCD, and to test whether a recombinant HO-1 will be efficacious in treating ACS in a preclinical model. Thus, in Aim #1, we will quantify blood HO-1 expression in patients and transgenic mice with SCD, and examine whether HO-1 expression in peripheral blood mononuclear cells is influenced by miR-494 expression and methylation of a highly conserved CpG site in HMOX1 the HO-1 gene. We will over-express and knock- down miR-494 in human peripheral blood mononuclear cells, and knock-out HO-1 activity in peripheral blood mononuclear cells of transgenic SCD mice, to determine the direct effects of these genetic/epigenetic alterations on HO-1 concentration in the plasma. We will perform whole genome next generation sequencing of SCD children with extreme levels of blood HO-1 level to identify novel whole genome sequence (WGS) variants that influence activity of this enzyme independent of age, miR-494 and HMOX1 methylation. In Aim #2, we will study a large cohort of SCD patients in Ghana to assess for the first time whether baseline blood HO-1 level, miR-494 level, HMOX1 methylation and WGS variants influence ACS risk. In Aim #3, we will use functional genomics to test the importance of HO-1 expression in blood cells in improving ACS survival, and test the efficacy of a novel truncated recombinant HO-1 molecule to rescue transgenic SCD mice from ACS. Data from this project has the potential to fundamentally change our understanding of how the body naturalizes the danger posed by circulating heme on organ function. In addition, it may provide a mechanism to explain the markedly variable ACS outcome in children and adults, with a tangible therapeutic strategy that can be implemented expeditiously using our novel HO-1 biologic.

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