Molecular Pathophysiology of Von Hippel Lindau (VHL) disease

Von Hippel Lindau (VHL) 病的分子病理生理学

基本信息

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
项目类别：
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

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

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项目摘要

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.

抽象的 von Hippel lindau（VHL）疾病是由VHL基因突变引起的常染色体显性疾病，通常，在不需要时，哪些功能有助于靶向缺氧诱导的因素降解。据报道，显性VHL突变导致促血管生成因子的过量产生，诱使患者发育多种肿瘤，包括残留的毛细血管血管瘤。在研究和管理VHL患者的许多挑战是广泛的表型变异性。为了例子，共享相同疾病引起突变的家庭成员可以显示出明显的差异他们的残留疾病表型。这些临床观察结果表明，有遗传修饰符影响患者残留疾病的严重程度。我们的中心在继承方面具有强大的研究专业知识视网膜疾病，我们已经在诱导的多能干细胞（IPSC）和基于CRISPR的基因组编辑，用于研究疾病病理生理学和新基因的发展基于理论。在此提案中，我们将使用患者来源的IPSC生成常规血管细胞 VHL病理生理学的研究。通过评估由永久性血管细胞的转录组同一家庭中具有相同疾病基因型但疾病表型截然不同的患者，我们假设我们将能够鉴定出残留血管肿瘤形成的新分子调节剂。这种疾病修饰符的识别将为我们提供新的疾病预后指标严重性和基于药物和基因治疗的新目标。