Genetics and Molecular Mechanisms Underlying Overgrowth Disorders of the Limb

肢体过度生长障碍的遗传学和分子机制

基本信息

批准号：
9915956
负责人：
Matthew P Harris
金额：
$ 36.73万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-07 至 2021-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9915956
关键词：
Address Affect Alleles Anatomy Animal Model Apical Ectodermal Ridge Area Behavior Biological Biology Catalytic Domain Cells Complex Cre driver Development Differentiation and Growth Digit structure Disease Distal Elements Embryo Event Gene Expression Genes Genetic Genetic Models Genetic Recombination Gigantism Growth Growth Disorders Growth Factor Hand Health Histopathology Human In Situ Knock-in Mouse Knowledge Lead Limb Development Limb structure Malignant Neoplasms Mechanics Mediating Mesenchymal Modality Modeling Molecular Morphology Mosaicism Mus Muscle Mutation Neoplasms Nerve Neurons Organ Organ Size PIK3CA gene Paracrine Communication Pathway interactions Patients Pattern Phenocopy Phenotype Phosphatidylinositols Phosphotransferases Physiological Potassium Channel Process Regulation Research Role Sensory Signal Transduction Somatic Mutation Specificity Structure Syndrome Testing Tissue Sample Tissues Transgenic Model Work Zebrafish appendage bone cell type digital exome sequencing foot gain of function mutation in vivo Model insight malformation mouse model mutant neoplastic neurotransmission novel novel strategies organ growth organ regeneration relating to nervous system response skeletal tissue soft tissue tissue repair

项目摘要

Summary The orchestration of growth and differentiation during development is essential for normal mechanical and physiological function of organs and appendages. Despite its importance, the regulation of how coordinated growth occurs such that proportion is maintained is not well understood. To gain insight into this process, we studied the congenital overgrowth disorder macrodactyly characterized by local giganticism of the digits of the hand and feet. Macrodactyly is a unique growth disorder in that the skeletal and soft tissue elements of the digits including nerve, vasculature, muscle and bone are enlarged, however organized such that larger digits form. Thus, patients with macrodactyly represent a unique biologic opportunity to explore fundamental mechanisms of how growth, size and proportion are coordinated within and between tissues. We have identified a specific somatic activating mutation in the catalytic subunit of phosphoinositide 3 kinase (PI3K), encoded by the gene PIK3CA, within affected tissue of macrodactyly patients. This mutation is also commonly found in cancer and other overgrowth disorders; thus, this mutation alone cannot explain the coordinated growth response observed in macrodactyly. How does this particular mutation lead to overgrowth that is coordinated and patterned during the development of the limbs? The restriction of overgrowth to the digits in these patients as opposed to the proximal limb, suggests a role for tissue interactions in the distal limb during development to regulate patterned growth and size. Additionally, we have identified potential modifier mutations arising in concert with PIK3CA that may be essential for PI3K regulation of overgrowth. We hypothesize that PI3K-mediated signaling coordinates growth through specific paracrine signaling from sensory neural tissues during development in a manner that is dependent on signaling between the apical ectodermal ridge (AER) and mesenchymal tissues during limb development. We propose to investigate the regulation of coordinated growth by PI3K through: 1) identification and localization of the affected cells and tissues containing mutant PIK3CA in macrodactyly patients and examination of the effect of these mutant cells on adjacent tissues; 2) use of novel zebrafish models to dissect the genetic and developmental causes of overgrowth though systematic analysis of newly identified secondary modifier mutations in regulating PIK3CA function and 3) the use of a conditional knockin mouse model of activated PIK3CA to test the sufficiency of increased PI3K signaling within specific tissues of the developing mouse limb to phenocopy macrodactyly. The proposed research will define the molecular and tissue level regulation of organ size and growth that will lead to new treatment modalities for a host of overgrowth and neoplastic conditions and yield new strategies for enhancing tissue repair and organ regeneration.

概括发育过程中生长和分化的协调对于正常的机械和分化至关重要器官和附肢的生理功能。尽管它很重要，但如何协调的监管增长如何维持比例尚不清楚。为了深入了解这个过程，我们研究了先天性巨指过度生长障碍，其特征是手指局部巨大化手和脚。巨指畸形是一种独特的生长障碍，其骨骼和软组织成分包括神经、脉管系统、肌肉和骨骼在内的手指都会增大，但组织方式使得较大的手指形式。因此，巨指患者代表了探索基本原理的独特生物学机会。组织内部和组织之间如何协调生长、大小和比例的机制。我们有确定了磷酸肌醇 3 激酶 (PI3K) 催化亚基中的特定体细胞激活突变，由巨指患者受影响组织内的基因 PIK3CA 编码。这种突变也很常见存在于癌症和其他过度生长疾病中；因此，仅此突变无法解释协调在巨指中观察到的生长反应。这种特殊的突变如何导致过度生长四肢发育过程中是否协调和有规律？过度增长对数字的限制这些患者而不是近端肢体，表明在治疗过程中远端肢体中组织相互作用的作用发育以调节模式生长和大小。此外，我们还确定了潜在的修饰符与 PIK3CA 协同产生的突变可能对于 PI3K 过度生长的调节至关重要。我们假设 PI3K 介导的信号传导通过特定的旁分泌信号传导来协调生长感觉神经组织在发育过程中的方式依赖于顶端之间的信号传导肢体发育过程中的外胚层嵴（AER）和间充质组织。我们建议调查 PI3K 通过以下方式调节协调生长：1) 识别和定位受影响的细胞和巨指症患者中含有突变 PIK3CA 的组织并检查这些突变细胞的作用邻近组织； 2）使用新型斑马鱼模型来剖析斑马鱼的遗传和发育原因通过系统分析新发现的调节 PIK3CA 的次级修饰突变来过度生长功能和3）使用激活PIK3CA的条件敲入小鼠模型来测试功能的充分性增加发育中小鼠肢体特定组织内的 PI3K 信号传导，以实现巨指的表型复制。这拟议的研究将定义器官大小和生长的分子和组织水平调节，这将导致针对一系列过度生长和肿瘤性疾病的新治疗方式，并产生新的策略增强组织修复和器官再生。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Modulation of bioelectric cues in the evolution of flying fishes.

DOI：
10.1016/j.cub.2021.08.054
发表时间：
2021-11-22
期刊：
CURRENT BIOLOGY
影响因子：
9.2
作者：
Daane, Jacob M.;Blum, Nicola;Lanni, Jennifer;Boldt, Helena;Iovine, M. Kathryn;Higdon, Charles W.;Johnson, Stephen L.;Lovejoy, Nathan R.;Harris, Matthew P.
通讯作者：
Harris, Matthew P.

Localized heterochrony integrates overgrowth potential of oncogenic clones.