Molecular Pathophysiology of Von Hippel Lindau (VHL) disease

摘要 Von Hippel Lindau病是一种常染色体显性遗传病，由VHL基因突变引起， 它通常在不需要的时候帮助靶向低氧诱导的降解因子。 据报道，显性VHL突变会导致促血管生成因子的过度产生， 使患者容易发生多种肿瘤，包括视网膜毛细血管瘤。在这些人中 研究和处理VHL患者的许多挑战是广泛的表型变异。为 例如，具有相同疾病导致突变的家庭成员在 他们的视网膜疾病表型。这些临床观察表明，有遗传修饰物可以 影响患者视网膜疾病的严重程度。我们中心在遗传方面有很强的研究专长 视网膜疾病，我们已经对诱导多能干细胞(IPSCs)和 基于CRISPR的基因组编辑在疾病病理生理研究和新基因开发中的应用 以治疗学为基础。在这项提案中，我们将使用患者来源的IPSCs来为 VHL的病理生理学研究。通过评估视网膜血管细胞的转录组 同一个家族中的患者具有相同的疾病基因但疾病表型非常不同，我们 假设我们将能够识别视网膜血管肿瘤形成的新的分子调节因子。 识别这些疾病修饰物将为我们提供两种新的疾病预后指标 药物和基于基因的治疗的严重性和新的目标。

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.