Molecular Pathophysiology of Von Hippel Lindau (VHL) disease

Von Hippel Lindau (VHL) 病的分子病理生理学

• 批准号: 10300318
• 负责人: Elaine Binkley
• 金额: $ 23.18万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10300318
• 关键词: 3-Dimensional; Adrenal Gland Neoplasms; Affect; Age; Alleles; Angiogenic Factor; Animals; Attention; Biological Assay; Blood Vessels; CRISPR correction; Cell Line; Cell Proliferation; Cells; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Development; Disease; Disease model; Ensure; Enzyme-Linked Immunosorbent Assay; Family; Family member; Functional disorder; Future; Gene Expression Regulation; Generations; Genes; Genetic; Genotype; Hereditary Disease; Hypoxia Inducible Factor; Immune; Impairment; Individual; Inherited; Injections; Kidney; Molecular; Mutation; Neoplasms in Vascular Tissue; Neuraxis; Ophthalmologist; Oxygen; Patients; Phenotype; Positioning Attribute; Production; Prognostic Marker; Reporting; Research; Retina; Retinal Diseases; Retinal Hemangioma; Sampling; Severities; Severity of illness; Spider nevus; Testing; Therapeutic; Tube; VHL gene; VHL mutation; Vascular Endothelial Cell; Von Hippel-Lindau Syndrome; Work; aged; base; cell motility; clinical examination; disease phenotype; disease-causing mutation; experimental study; genome editing; in vitro Assay; in vivo; induced pluripotent stem cell; mutant; new therapeutic target; novel; novel therapeutics; prognostic; retina blood vessel structure; single-cell RNA sequencing; therapeutic gene; therapeutic target; transcriptome; transcriptome sequencing; tumor; tumorigenic; wound closure

ABSTRACT Von Hippel Lindau (VHL) disease is an autosomal dominant condition caused by mutations in the VHL gene, which normally functions to help target hypoxia-inducible factors for degradation when not required. Dominant VHL mutations have been reported to result in excessive production of pro-angiogenic factors, predisposing patients to development of a number of tumors including retinal capillary angiomas. Among the many challenges in studying and managing patients with VHL is the extensive phenotypic variability. For instance, family members that share the same disease causing mutation can display significant variability in their retinal disease phenotype. These clinical observations suggest that there are genetic modifiers that influence the severity of the patient’s retinal disease. Our center has strong research expertise in inherited retinal diseases, and we have performed extensive work with induced pluripotent stem cells (iPSCs) and CRISPR based genome editing for both the study of disease pathophysiology and development of novel gene based therapeutics. In this proposal we will use patient-derived iPSCs to generate retinal vascular cells for the study of VHL pathophysiology. By evaluating the transcriptome of retinal vascular cells generated from patients within the same family who have the same disease genotype but very different disease phenotypes, we hypothesize that we will be able to identify novel molecular regulators of retinal vascular tumor formation. Identification of such disease modifiers would provide us with both new prognostic indicators of disease severity and new targets for drug and gene-based treatments.

摘要 Von Hippel Lindau（VHL）病是由VHL基因突变引起的常染色体显性疾病， 其通常用于在不需要时帮助靶向低氧诱导因子以降解。 据报道，显性VHL突变导致促血管生成因子的过度产生， 使患者易患许多肿瘤，包括视网膜毛细血管瘤。中 研究和管理VHL患者的许多挑战是广泛的表型变异性。为 例如，具有相同致病突变的家庭成员在以下方面可能表现出显著的变异性： 他们的视网膜疾病表型。这些临床观察表明，有遗传修饰剂， 影响患者视网膜疾病的严重程度。我们的中心在遗传性疾病方面有很强的研究专长， 视网膜疾病，我们已经进行了大量的工作与诱导多能干细胞（iPSC）， 基于CRISPR的基因组编辑用于疾病病理生理学研究和新基因开发 基于治疗。在这项提议中，我们将使用患者来源的iPSC来产生视网膜血管细胞， VHL病理生理学研究。通过评估视网膜血管细胞的转录组， 同一家族中具有相同疾病基因型但疾病表型非常不同的患者，我们 假设我们将能够鉴定视网膜血管肿瘤形成新分子调节剂。 鉴定这些疾病修饰因子将为我们提供新的疾病预后指标， 严重性和药物和基因治疗的新靶点。