A novel regulator of breast development

乳房发育的新型调节剂

基本信息

批准号：
8764122
负责人：
RUTH A. KERI
金额：
$ 19.81万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-11 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8764122
关键词：
8p22 Adult Affect Bone Development Breast Breast Cancer Prevention Breast Diseases Breast Feeding Candidate Disease Gene Centers for Disease Control and Prevention (U.S.)Child Chromosomes Congenital Abnormality Custom DNA Defect Development Disease Embryo Endocrine Engineering Epithelial Exhibits Exogenous Factors Exploratory/Developmental Grant Extended Family Family Family member Female Funding Future Gene Mutation Genes Genome Goals Hair Hormones Human Human Development Infant Inheritance Patterns Inherited Intervention Intrinsic factor Knock-in Mouse Lactation Libraries Malignant Neoplasms Mammals Mammary Gland Parenchyma Mammary gland Maps Mental Health Mesenchymal Mesenchyme Methods Milk Modeling Molecular Morphogenesis Mothers Mus Mutation Nature Nipples Pathway interactions Pattern Phenotype Population Postpartum Period Production Property Research Resources Single Nucleotide Polymorphism Map Syndrome Technology Tissue-Specific Gene Expression Tissues Tooth structure Tumor Subtype United States Woman Work appendage autosomal dominant trait base cancer initiation cancer risk deep sequencing improved male malignant breast neoplasm mammary epithelium mammary gland development men mouse genome mouse model novel public health relevance statistics stem tool trait tumor progression zinc finger nuclease

项目摘要

DESCRIPTION (provided by applicant): Mammary gland development is essential for the viability of most mammals and the sustainability of many human populations. In addition, exogenous and intrinsic factors that control mammary morphogenesis have repeatedly been implicated in regulating breast cancer risk, tumor subtype, and/or metastatic progression. Thus, identifying the networks that control mammary morphogenesis is necessary for sustaining human development and discovering additional contributors to breast disease. We have recently identified a novel extended family with a breast developmental defect. Half of all males and females in this family have congenital nipple dysmorphia and females fail to develop breasts. The trait follows an autosomal dominant inheritance pattern, does not correspond to any previously described breast developmental defect, and has been mapped to a single chromosomal region that does not contain any established breast development genes. Thus, this family provides a unique opportunity to discover a novel mutation/gene that controls breast development and potentially cancer. With this proposal, deep sequencing will be performed on affected and unaffected family members to identify the specific mutation in this family that segregates with the amastia phenotype. The tissue specific expression of this gene will then be assessed throughout normal mammary gland development in the mouse and in adult human breast tissue. Lastly, we will develop a novel genetically- manipulated mouse model wherein the human mutation has been engineered in the mouse genome. These mice will be a vital resource for establishing the function of the identified gene in breast development and the impact of the human mutation on that function. Upon completion, this R21 proposal will uncover a completely new pathway controlling breast morphogenesis and generate necessary tools for future analyses of the mechanism(s) by which it controls development and possibly cancer.

描述（由申请人提供）：乳腺发育对于大多数哺乳动物的生存能力和许多人口的可持续性至关重要。此外，控制乳腺形态发生的外源性和内在因素反复与调节乳腺癌风险，肿瘤亚型和/或转移性进展有关。因此，确定控制乳腺形态发生的网络对于维持人类发育并发现乳房疾病的其他贡献是必要的。我们最近确定了一个具有乳房发育缺陷的新型大家庭。这个家庭中的所有男性和女性中有一半患有先天性乳头畸形，而女性则无法发育乳房。该性状遵循常染色体显性遗传模式，与任何先前描述的乳房发育缺陷不符，并且已映射到一个不包含任何已建立乳腺发育基因的染色体区域。因此，这个家庭提供了一个独特的机会，可以发现一种新型的突变/基因控制乳腺癌的发育和潜在的癌症。通过此建议，将对受影响和未受影响的家庭成员进行深层测序，以识别该家族中与amastia表型分离的特定突变。然后，将在小鼠和成年人类乳腺组织中的正常乳腺发育中评估该基因的组织特异性表达。最后，我们将开发一种新型的遗传操纵小鼠模型，其中人类突变已在小鼠基因组中进行了设计。这些小鼠将是确定鉴定基因在乳腺发育中的功能以及人类突变对该功能的影响的重要资源。完成后，该R21提案将发现一条全新的途径，以控制乳房形态发生，并生成必要的工具，以对其控制发育和可能癌症的机制进行以后的分析。