Patient-Oriented Research in Pediatric Hematology

这是一份修订后的K24资金竞争续订申请。应聘者是一名儿科血液学家和遗传学家，受过生物化学和分子生物学方面的基础科学培训，并具有儿科血液、血脂和血管疾病的临床研究背景。该奖项的主要目标是在几个正在进行的儿科血液疾病研究项目中为指导提供受保护的时间。从长远来看，目标是将PI建立为学生、住院医生、研究员和对以患者为导向的儿科血液学和遗传学研究感兴趣的初级成员的高级导师。研究环境是波士顿儿童医院的儿科血液学/肿瘤学项目 达纳·法伯癌症研究所。指导的机会包括哈佛本科生、当地和来访的医学生、住院医生和研究员(不限于血液学方面的人员)，以及从事学术医学和以患者为导向的研究的初级教员。在这一修订的应用程序中，重点是对血液疾病的遗传病理生理学进行“床边到工作台”的分析，分为两个项目。第一个目标/项目是进一步描述由于高亲和力硫胺转运体SLC19A2基因缺陷引起的罕见的人类疾病-硫胺素反应性巨幼细胞性贫血。在第一个K24支持期，候选人的实验室确定了致病基因和许多患者的突变。对SLC19A2基因突变的进一步研究将在最近发现的TRMA患者和相关疾病中进行。[~H]硫胺素摄取研究和[1，2-13C]葡萄糖稳定同位素代谢分析，这两种方法都是在最初的赠款期间开发的，将对具有感兴趣的TRMA变异的患者的细胞进行研究，包括一个没有检测到SLC19A2突变的患者。在第一个K24期为人类不可能进行的病理生理学研究开发的TRMA小鼠模型将被用于进一步阐明这种疾病的病理生理学的骨髓研究。将TRMA小鼠的骨髓移植到正常小鼠体内，将确定骨髓缺陷是否为细胞固有的。第二个目标是候选基因测序 将用于确定儿童医院血液学项目中确定的罕见遗传性血液疾病的原因。使用这种方法，已经研究了几种独特的凝血和贫血疾病。

This is a revised competing renewal application for K24 funding. The candidate is a pediatric hematologist and geneticist, with basic science training in biochemistry and molecular biology, and a clinical research background in pediatric blood, lipid and vascular disorders. The primary goal for this award is to provide protected time for mentoring in the setting of several ongoing patient-oriented research projects in pediatric blood disorders. In the long run, the goal is to establish the PI as a senior mentor for students, residents, fellows, and junior members interested in patient-oriented research in pediatric hematology and genetics. The study environment is the Pediatric Hematology/Oncology program of Children's Hospital Boston and Dana Farber Cancer Institute. Opportunities for mentoring include Harvard undergraduates, local and visiting medical students, residents and fellows not limited to those in hematology, and junior faculty members launching careers in academic medicine and patient oriented research. In this revised application, the focus is on "bedside to bench" analysis of the genetic pathophysiology of blood disorders, divided into two projects. The first aim/project is to further characterize the rare human disorder, thiamine-responsive megaloblastic anemia, due to defects in the gene for high-affinity thiamine transporter, SLC19A2. In the first K24 support period, the candidate's lab identified the causative gene and many patients' mutations. Further studies of mutations of this SLC19A2 gene will be performed on recently identified patients with TRMA, and related disorders. [3H]Thiamine uptake studies and stable isotope metabolic profiling with [1,2-13C]glucose, both methods developed in the initial grant period, will be pursued for cells from patients with interesting TRMA variants, including one with no detectable SLC19A2 mutation. A murine model of TRMA, developed in the first K24 period for pathophysiology studies not possible in humans, will be utilized for marrow studies that will further elucidate the pathophysiology of the disorder. Marrow transplantation from TRMA mice into normal will determine if the marrow defect is cell-intrinsic. In the second aim, candidate gene sequencing will be used to identify the cause of rare inherited blood diseases identified in the hematology program at Children's Hospital. Using this approach, several unique disorders of blood clotting and anemia have been studied.