Investigation of ERBB2 and ERBB3 in hematopoiesis and predisposition to hematologic disease

项目摘要 罕见的遗传性疾病为识别人类疾病基因提供了独特的机会， 深入了解疾病的病理生理学，通常更好地了解基本的生物过程。这 可以改善对患有多种疾病的患者的诊断和治疗。这个目标 这项计划的目的是研究血液病家族易感性的潜在机制， 骨髓增生异常综合征（MDS）和骨髓增生性肿瘤（MPN）。这些恶性肿瘤是 传统上认为是由于获得性体细胞突变而发生的，随着年龄的增长而变得更加频繁。然而，在这方面， 越来越多的证据表明，相当多的患者携带遗传性遗传变异， 导致成年期恶性表型的发生。了解这一过程的病因 仍然是科学研究的重要领域。 Braunstein博士是一位长期对人类遗传学感兴趣的物理学家。他获得了 在进入约翰霍普金斯医学院临床研究之前获得分子遗传学博士学位。他 在他的奖学金培训期间的研究工作导致ERBB3被鉴定为新的候选物 MDS易感基因在完成他的奖学金，博士布劳恩斯坦加入了教师在该司 他在约翰霍普金斯大学的血液学教授，并发起了一项研究计划，调查遗传易感性， 血液病这笔赠款将支持博士布劳恩斯坦在他的道路上成为一个独立的 研究员，并协助他在他的目标，服务患者罕见的遗传性血液病。 以前的工作涉及调查一个大家庭与遗传性红细胞MDS揭示， ERBB3基因中的错义突变作为诱发性病理变异。这些数据导致了 ERBB 3或其他ERBB基因的突变可能发生在相关疾病中，如家族性MPN， 约占所有MPN病例的10%。这一假设得到了生殖系的鉴定的支持。 ERBB2变异与遗传性MPN家族疾病共分离。最重要的假设是 这种应用是ERBB 3信号通路的激活改变了正常的造血， 在血液恶性肿瘤如MDS和MPN中观察到克隆进展。目标1：分析 ERBB2和ERBB3基因在血液发育中的表达和功能， 造血细胞和诱导多能干细胞（iPSC）模型。这些细胞的基因改造将 分离这些基因在造血过程中的作用。目标2的目标是调查 ERBB 2和ERBB 3在MDS和MPN易感性中的作用。两个患者队列的靶向测序 将进行被认为富集ERBB途径突变的基因组测序。此外，ERBB3信号异常可能与ERBB3信号异常有关。 将使用患者来源的iPSC模型和小鼠模型研究造血系统， 阐明克隆进展的机制。

Project Summary Rare inherited disorders provide unique opportunities to identify disease genes in humans, providing insight into disease pathophysiology and often a better understanding of essential biological processes. This can lead to improved diagnosis and treatment of patients with a broad range of disorders. The goal of this proposal is to study the mechanisms underlying familial predisposition to hematological diseases such as myelodysplastic syndrome (MDS) and the myeloproliferative neoplasms (MPN). These malignancies are traditionally thought to occur due to acquired somatic mutations that become more frequent with age. However, a growing body of evidence indicates that a significant number of patients harbor inherited genetic variants that contribute to the onset of the malignant phenotype in adulthood. Understanding the etiology of this process remains an important area of scientific research. Dr. Braunstein is a physician-scientist with a long-standing interest in human genetics. He obtained his PhD in molecular genetics prior to entering clinical fellowship at Johns Hopkins School of Medicine. His research efforts during his fellowship training led to the identification of ERBB3 as a novel candidate predisposition gene in MDS. Upon completion of his fellowship, Dr. Braunstein joined the faculty in the Division of Hematology at Johns Hopkins and initiated a research program to investigate genetic predisposition to hematologic diseases. This grant will support Dr. Braunstein in his path toward becoming an independent investigator and assist him in his goal of serving patients with rare inherited hematologic diseases. Previous work involving investigation of a large family with inherited erythroid MDS revealed a missense mutation in the ERBB3 gene as the predisposing pathological variant. This data led to the premise that mutations in ERBB3, or other ERBB genes, may occur in related diseases such as familial MPN, which comprise approximately 10% of all MPN cases. This hypothesis is supported by the identification of a germline variant in ERBB2 co-segregating with disease in a family with inherited MPN. The overarching hypothesis of this application is that activation of the ERBB3 signaling pathway alters normal hematopoiesis and accelerates clonal progression observed in hematologic malignancies such as MDS and MPN. Aim 1 proposes to analyze the expression and function of the ERBB2 and ERBB3 genes in blood development using both primary hematopoietic cells and an induced pluripotent stem cell (iPSC) model. Genetic modification of these cells will be performed to isolate the role of these genes during hematopoiesis. The goal of Aim 2 is to investigate the role of ERBB2 and ERBB3 in predisposition to MDS and MPN. Targeted sequencing of two patient cohorts thought to be enriched for ERBB pathway mutations will be performed. Further, abnormal ERBB3 signaling in the hematopoietic system will be studied using both a patient-derived iPSC model and a mouse model in order to elucidate the mechanisms underlying clonal progression.