Patient-Oriented Research in Pediatric Hematology

这是K24资金的修订后的竞争性续期申请。候选人是一名儿科血液学家和遗传学家，在生物化学和分子生物学方面接受过基础科学培训，并具有儿科血液，脂质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以患者为导向的儿科血液疾病研究项目的背景下提供受保护的指导时间。从长远来看，我们的目标是建立PI作为学生，居民，研究员，并在儿科血液学和遗传学的患者为导向的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，当地和访问医学生，居民和研究员不限于那些在血液学，和初级教师启动职业生涯在学术医学和病人为导向的研究。在这个修订后的应用程序，重点是“床边到板凳”的血液疾病的遗传病理生理学分析，分为两个项目。第一个目标/项目是进一步表征罕见的人类疾病，硫胺素反应性巨幼细胞性贫血，由于高亲和力硫胺素转运蛋白SLC 19 A2基因的缺陷。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。将对最近发现的TRMA和相关疾病患者进行SLC 19 A2基因突变的进一步研究。[3 H]硫胺素摄取研究和[1，2 - 13 C]葡萄糖的稳定同位素代谢分析，这两种方法都是在最初的资助期开发的，将对来自具有感兴趣的TRMA变体的患者的细胞进行研究，包括一个没有可检测到的SLC 19 A2突变的患者。在第一个K24期开发的TRMA小鼠模型用于人类不可能进行的病理生理学研究，将用于骨髓研究，进一步阐明该疾病的病理生理学。将TRMA小鼠的骨髓移植到正常小鼠中将确定骨髓缺陷是否是细胞固有的。第二个目标是候选基因测序 将用于确定罕见的遗传性血液病的原因，在儿童医院的血液学项目中确定。使用这种方法，已经研究了几种独特的血液凝固和贫血疾病。

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.