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，并获得了内科和临床遗传学的董事会认证。该赠款提案旨在为候选人提供指导的培训经验，这将促进她作为专注于卟啉症的独立临床研究人员的发展，这是血红素生物合成的先天错误。这些疾病的临床，生化和分子研究经验丰富。指导者在指导研究员和初级教职员工方面有着良好的记录。因此，将向申请人提供的指导计划以及实验室和临床研究环境将有助于她作为独立研究人员的发展。拟议的研究将重点放在促红细胞原生质畸形（EPP） - 表型，这是一组遗传异源的光诱导，严重的皮肤斑岩。迄今已确定了EPP - 表型的三个亚型：1）由于铁chelatase（Fech）基因中的“功能损失”突变引起的常染色体隐性EPP，X连锁原生石（XLP），新近识别的子典型导致“ X-spec erise of frofunific Drifatific” X-spec ersect offfific spec spec ersect offific spec spec spec spec the sprection spec spec s-sprection the x-s-sprection the x-s-s-sprifation”氨基乙酸合酶（ALAS2）基因和3）亚型具有升高的红细胞原核，皮肤光敏性以及正常的FECH和ALAS2等位基因。拟议的研究最初将识别，表征和确定FECH和ALAS2突变的频率，从而导致100多名未与卟啉财团一起入学的无关患者中的EPP - 表型。在突变确认的EPP和XLP的患者中，将确定自然史，临床光谱，生活质量和红细胞原磷脂水平。在XLP中，将在雌性杂合子中确定临床表现的不存在，存在和严重程度，以及红细胞自由和锌 - 丙啉丁蛋白的水平，与在X-kewrys x-kewry skewron fy s se-kewron fy sys heterogygote的造血细胞中表达的突变ALAS2等位基因的比例相关。将在EPP和XLP患者中进行一项新型FDA批准的试验研究，以确定与ALAS2的共同因素结合的异念珠菌是否可以降低ALAS2的活性，从而降低摄取XLP XLP的嗜红细胞蛋白质的形成。该奖项提供的受保护时间将使申请人成为卟啉症诊断和管理方面的专家，从而促进了申请人的目标，即建立独立的研究职业，专注于卟啉病发病机理研究和新型治疗的发展。