Clinical and Molecular Studies of the Erythropoietic Protoporphyria Phenotype

描述（由申请人提供）：候选人Manisha Balwani MD，MS，是西奈山医学院遗传学和基因组科学系的助理教授，并获得内科和临床遗传学委员会认证。该拨款提案旨在为候选人提供指导培训经验，以促进她作为一名独立的临床研究人员的发展，专注于卟啉，血红素生物合成的先天性错误。导师们在这些疾病的临床、生化和分子研究方面经验丰富。导师们在指导研究员和初级教师进行转化研究、临床试验和药物开发方面有着良好的记录。因此，导师计划和实验室和临床研究环境，将提供给申请人将促进她作为一个独立的研究人员的发展。拟议的研究将集中在红细胞生成性原卟啉症（EPP）-表型，一组遗传异质性光诱导，严重的皮肤卟啉症。迄今为止，已鉴定出EPP表型的三种亚型：1）由于亚铁螯合酶（FECH）基因中的“功能丧失”突变引起的常染色体隐性EPP，2）X连锁原卟啉症（XLP），一种由X连锁红细胞特异性d-氨基乙酰丙酸合酶（ALAS 2）基因的“功能获得”突变引起的新识别的亚型，和3）具有升高的红细胞原卟啉的亚型，皮肤光敏性，正常FECH和ALAS 2等位基因。拟议的研究将首先识别，表征和确定FECH和ALAS 2突变的频率，这些突变导致超过100名已经入组卟啉病联盟的无关患者的EP表型。将在突变证实的EPP和XLP患者中确定自然史、临床谱、生活质量和红细胞原卟啉水平。在XLP中，将在女性杂合子中确定临床表现的存在或不存在以及严重程度，以及红细胞游离原卟啉和锌原卟啉的水平，并与由于随机X染色体失活的偏斜而在来自个体杂合子的造血细胞中表达的突变ALAS 2等位基因的比例相关。FDA批准的一项新的初步研究将在EPP和XLP患者中进行，以确定与ALAS 2的辅助因子磷酸吡哆醛结合的异烟肼是否可以降低ALAS 2的活性，从而减少导致XLP表现的红细胞原卟啉的形成。该奖项提供的受保护时间将允许申请人成为卟啉症诊断和管理方面的专家，促进申请人建立独立研究职业生涯的目标，专注于卟啉症发病机制的研究和新疗法的开发。

DESCRIPTION (provided by applicant): The candidate, Manisha Balwani MD, MS, is an Assistant Professor in the Department of Genetics and Genomic Sciences at the Mount Sinai School of Medicine and is board certified in Internal Medicine and Clinical Genetics. This grant proposal is designed to provide the candidate with a mentored training experience that will facilitate her development as an independent clinical researcher focused on the Porphyrias, the inborn errors of heme biosynthesis. The Mentors are experienced in the clinical, biochemical, and molecular studies of these diseases. The Mentors have a strong record in mentoring fellows and junior faculty in translational research, clinical trials and drug development. Thus, the mentoring program and laboratory and clinical research environment that will be available to the applicant will facilitate her development as an independent researcher. The proposed research will focus on the Erythropoietic Protoporphyria (EPP)-phenotype, a group of genetically heterogenous photo-induced, severe, cutaneous porphyrias. Three subtypes of the EPP-phenotype have been identified to date: 1) autosomal recessive EPP due to "loss- of-function" mutations in the ferrochelatase (FECH) gene, 2) X-linked Protoporphyria (XLP), a newly recognized subtype resulting from "gain-of-function" mutations of the X-linked erythroid-specific d- aminolevulinate synthase (ALAS2) gene, and 3) a subtype with elevated erythrocyte protoporphyrins, cutaneous photosensitivity, and normal FECH and ALAS2 alleles. The proposed studies will initially identify, characterize, and determine the frequency of the FECH and ALAS2 mutations causing the EPP-phenotype in over 100 unrelated patients already enrolled in the Porphyria Consortium. The natural history, clinical spectrum, quality of life, and erythrocyte protoporphyrin levels will be determined in patients with mutation- confirmed EPP and XLP. In XLP, the absence or presence and severity of clinical manifestations, and the levels of erythrocyte free- and zinc-protoporphyrins will be determined in female heterozygotes and correlated with the proportion of mutant ALAS2 alleles expressed in hematopoietic cells from individual heterozygotes due to skewing of random X-chromosomal inactivation. A novel FDA-approved pilot study will be conducted in patients with EPP and XLP to determine if Isoniazid, which binds to pyridoxal phosphate, a co-factor of ALAS2, can decrease the activity of ALAS2, thereby reducing the formation of erythrocyte protoporphyrin, which causes the XLP manifestations. The protected time afforded by this award would permit the applicant to become expert in the diagnosis and management of the porphyrias, facilitate the applicant's goal of establishing an independent research career focused on studies of porphyria pathogenesis and the development of novel treatments.