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：
10470845
负责人：
Elaine Binkley
金额：
$ 18.73万
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/10470845
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 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 prognostic indicator retina blood vessel structure single-cell RNA sequencing therapeutic gene therapeutic target transcriptome transcriptome sequencing tumor tumorigenic wound closure

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) 病是一种常染色体显性遗传疾病，由 VHL 基因突变引起，当不需要时，其正常功能有助于靶向缺氧诱导因子的降解。据报道，显性 VHL 突变会导致促血管生成因子的过度产生，使患者易患多种肿瘤，其中包括视网膜毛细血管瘤。研究和管理 VHL 患者的许多挑战是广泛的表型变异。例如，患有相同疾病的家庭成员可能会表现出显着的变异性他们的视网膜疾病表型这些临床观察表明存在一些遗传修饰因素。影响患者视网膜疾病的严重程度我们中心在遗传方面拥有强大的研究专业知识。视网膜疾病，我们在诱导多能干细胞（iPSC）和基于 CRISPR 的基因组编辑用于疾病病理生理学研究和新基因开发在本提案中，我们将使用患者来源的 iPSC 来生成视网膜血管细胞。通过评估视网膜血管细胞的转录组来研究 VHL 病理生理学。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，我们我们将能够识别视网膜血管肿瘤形成的新分子调节因子。识别此类疾病修饰因素将为我们提供新的疾病预后指标严重程度以及药物和基因治疗的新目标。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Intrafamilial Variability of Ocular Manifestations of von Hippel-Lindau Disease.

DOI：
10.1016/j.oret.2021.08.005
发表时间：
2022-01
期刊：
OPHTHALMOLOGY RETINA
影响因子：
4.5
作者：
Bowen, Randy Christopher;Boldt, H. Culver;Mullins, Robert F.;Field, Matthew G.;Affatigato, Louisa M.;Hoffmann, Jeremy M.;Folk, James C.;Gehrs, Karen M.;Han, I. A. N. C.;Sohn, Elliott H.;Russell, Stephen R.;Stone, Edwin M.;Tucker, Budd A.;Binkley, Elaine M.
通讯作者：
Binkley, Elaine M.