Clinical and Molecular Studies of the Erythropoietic Protoporphyria Phenotype

红细胞生成性原卟啉症表型的临床和分子研究

基本信息

批准号：
8509354
负责人：
MANISHA BALWANI
金额：
$ 17.84万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8509354
关键词：
Acute Adolescent Adopted Affect Age of Onset Alleles Aminolevulinate Androgen Receptor Applications Grants Award Binding Biochemical Biochemical Genetics Biological Assay Cells Characteristics Child Childhood Clinical Clinical Investigator Clinical Research Clinical Trials Collaborations Consent Cutaneous Data Data Analyses Development Diagnosis Disease Effectiveness Enrollment Environment Erythrocytes Erythroid Erythropoietic Protoporphyria Exons FDA approved Faculty Female Frequencies Funding Gene Mutation Genes Genetic Genetic Heterogeneity Genetic Polymorphism Genomics Genotype Goals Hematopoietic Heterozygote In Vitro Inborn Genetic Diseases Individual Internal Medicine Laboratory Research Link Liver Dysfunction Liver Failure Mentors Metabolic Diseases Missense Mutation Molecular Mutation Natural History Nature Neurologic Oral Parents Pathogenesis Patient Recruitments Patients Phenotype Photosensitivity Pilot Projects Plasma Porphyrias Protocols documentation Protoporphyrins Pyridoxal Phosphate Quality of life Questionnaires Rare Diseases Recording of previous events Recruitment Activity Research Research Personnel Residual state Safety Science Severities Site Skin Techniques Therapy Clinical Trials Time Training Training Programs Translational Research United States National Institutes of Health base career career development design drug development erythropoietic protoporphyria porphyria exome sequencing experience ferrochelatase gain of function mutation heme biosynthesis improved infancy isoniazid loss of function loss of function mutation medical schools mutant novel novel therapeutic intervention pilot trial professor programs psychosocial public health relevance zinc protoporphyrin

项目摘要

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.

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，以促进她作为一名专注于血红素生物合成的先天性错误——卟啉症的独立临床研究人员的发展。导师在这些疾病的临床、生化和分子研究方面经验丰富。导师们在指导转化研究、临床试验和药物开发领域的研究员和初级教师方面拥有良好的记录。因此，申请人可以获得的指导计划以及实验室和临床研究环境将促进她作为独立研究人员的发展。拟议的研究将重点关注红细胞生成性原卟啉症（EPP）表型，这是一组遗传异质性光诱导的严重皮肤卟啉症。迄今为止，已鉴定出 EPP 表型的三种亚型：1) 由于铁螯合酶 (FECH) 基因“功能丧失”突变而导致的常染色体隐性 EPP，2) X 连锁原卟啉症 (XLP)，一种新识别的亚型由 X 连锁红细胞特异性 d-氨基乙酰丙酸合酶 (ALAS2) 基因的“功能获得”突变引起，以及 3) 具有以下特征的亚型红细胞原卟啉升高、皮肤光敏性以及 FECH 和 ALAS2 等位基因正常。拟议的研究将首先在已加入卟啉症联盟的 100 多名无关患者中识别、描述和确定导致 EPP 表型的 FECH 和 ALAS2 突变的频率。将确定突变确认的 EPP 和 XLP 患者的自然史、临床谱、生活质量和红细胞原卟啉水平。在 XLP 中，将确定女性杂合子中临床表现的存在与否以及临床表现的严重程度以及红细胞游离原卟啉和锌原卟啉的水平，并与个体杂合子的造血细胞中表达的突变 ALAS2 等位基因的比例相关。随机 X 染色体失活。 FDA 批准的一项新的试点研究将在 EPP 和 XLP 患者中进行，以确定与 ALAS2 辅助因子磷酸吡哆醛结合的异烟肼是否可以降低 ALAS2 的活性，从而减少红细胞原卟啉的形成，从而减少红细胞原卟啉的形成。导致XLP表现。该奖项提供的受保护时间将使申请人成为卟啉症诊断和治疗方面的专家，促进申请人建立专注于卟啉症发病机制研究和新疗法开发的独立研究生涯的目标。