Investigating mechanisms of tissue polarity during development and disease

研究发育和疾病过程中组织极性的机制

基本信息

批准号：
10751262
负责人：
Jazmin Stenson
金额：
$ 3.46万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-11-01 至 2026-10-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10751262
关键词：
Adhesions Anterior Biochemical Biological Biological Assay Biological Models Cadherin Domain Cadherins Cardiomyopathies Cell Adhesion Cell Aggregation Cell Culture System Cell membrane Cells Cellular biology Co-Immunoprecipitations Congenital Heart Defects Defect Development Disease EGF gene Embryo Environment Epidermis Failure Family member Fellowship Fluorescence Fluorescence Polarization Genes Genetic Goals Hair Hair follicle structure Human Human Development Image Intercellular Junctions Labyrinth Maps Mediating Medicine Membrane Proteins Mentors Microscopy Modeling Molecular Molecular Biology Mus Mutation Neural Tube Defects Neural tube Optics Organ Pathogenicity Pathway interactions Patients Pattern Polarization Microscopy Proline Proteins Regulation Reporter Research Sagittaria Side Signal Pathway Signal Transduction Skin Solid Spinal Dysraphism Testing Tissues Training Whole Organism Zebrafish career development cell behavior ciliopathy cohort college developmental disease fly genetic approach human disease in vivo in vivo optical imaging insight keratinocyte mutant novel planar cell polarity protein function receptor zygote

项目摘要

PROJECT SUMMARY Organ formation and tissue patterning during human development rely on collective and oriented cell behaviors. Planar cell polarity (PCP), a signaling pathway conserved from flies to humans, governs this coordination between neighboring cells. PCP is well represented by the ordered alignment of body hairs across the mammalian skin along the anterior-posterior body axis. Deficiencies in PCP protein function result in severe developmental defects including cardiomyopathies, ciliopathies and neural tube defects such as spina bifida. How PCP pathway disruption results in developmental disorders remains poorly understood. Importantly, PCP disruption resulting in developmental defects and embryonic lethality in mice also results in a failure to properly pattern the embryonic epidermis, thus the mouse skin is a suitable model system with and hair follicle polarity being a tractable read-out of PCP function. A defining feature of PCP is the asymmetric localization of core PCP proteins Frizzled 6 (Fz6) and Van Gogh like protein 2 (Vangl2) at cell-cell borders. Intercellular interactions of atypical cadherin Celsr1 is required for the Fz6 and Vangl2 localization at cell borders. Yet, we do not understand how Celsr1 adhesion organizes asymmetric PCP junctions or how this is regulated during development. The need to understand how Celsr1 functions as a driver of Fz6-Vangl2 asymmetry at junctions is underscored by the recent identification of novel, predicted pathogenic, Celsr1 mutations in patients with neural tube and congenital heart defects. The overall goal of this proposal is to better understand how these disease-associated Celsr1 mutations, particularly those that map to the Celsr1 domains responsible for cell adhesion, contribute to human developmental disorders. Using the murine epidermis as model system for PCP function, along with cell and molecular biology, biochemical, advanced optical imaging and in vivo genetic approaches, I will test the hypothesis that disease-associated Celsr1 mutations perturb Celsr1 cell adhesion and alter the establishment of PCP asymmetry during development. This hypothesis will be interrogated in the following specific aims: 1) Determine how disease-associated Celsr1 mutations impact Celsr1 adhesion and signaling, and 2) Determine how disease-associated Celsr1 mutations impact PCP establishment. The proposed aims will reveal pathomechanisms of developmental disorders that target Celsr1 function while also providing key insight into how Celsr1 regulates PCP establishment. Fellowship support to complete the proposed research and crafted training plan, along with guidance from my mentoring team and the environment at the Penn State College of Medicine, will be instrumental in my career development toward my goal of leading an independent and diverse research team.

项目概要人类发育过程中的器官形成和组织模式依赖于集体和定向的细胞行为。平面细胞极性（PCP）是从果蝇到人类保守的信号通路，控制着这种协调相邻小区之间。 PCP 的特征是全身毛发有序排列。沿着身体前后轴的哺乳动物皮肤。 PCP 蛋白功能缺陷会导致严重的发育缺陷，包括心肌病、纤毛病和神经管缺陷，如脊柱裂。 PCP 通路破坏如何导致发育障碍仍知之甚少。重要的是，PCP 导致小鼠发育缺陷和胚胎致死的破坏也会导致无法正确地形成胚胎表皮图案，因此小鼠皮肤是具有毛囊极性的合适模型系统是 PCP 功能的易于处理的读数。 PCP 的一个决定性特征是核心 PCP 的非对称本地化细胞-细胞边界处的蛋白质卷曲 6 (Fz6) 和梵高样蛋白质 2 (Vangl2)。细胞间相互作用 Fz6 和 Vangl2 在细胞边界的定位需要非典型钙粘蛋白 Celsr1。然而，我们不明白 Celsr1 粘附如何组织不对称 PCP 连接或在发育过程中如何对其进行调节。这需要了解 Celsr1 如何作为连接处 Fz6-Vangl2 不对称性的驱动因素最近在神经管患者中发现了新的、预测的致病性 Celsr1 突变先天性心脏缺陷。该提案的总体目标是更好地了解这些与疾病相关的疾病如何 Celsr1 突变，特别是那些映射到负责细胞粘附的 Celsr1 结构域的突变，有助于人类发育障碍。使用小鼠表皮作为 PCP 功能的模型系统以及细胞和分子生物学、生物化学、先进光学成像和体内遗传方法，我将测试假设疾病相关的 Celsr1 突变会扰乱 Celsr1 细胞粘附并改变发育过程中 PCP 不对称。该假设将在以下具体目标中受到质疑：1）确定疾病相关的 Celsr1 突变如何影响 Celsr1 粘附和信号传导，以及 2) 确定疾病相关的 Celsr1 突变如何影响 PCP 建立。拟议的目标将揭示针对 Celsr1 功能的发育障碍的病理机制，同时还提供了关键的见解 Celsr1 如何调节 PCP 建立。奖学金支持完成拟议的研究和精心设计培训计划，以及我的导师团队的指导和宾夕法尼亚州立大学的环境医学，将有助于我的职业发展，实现领导独立和多元化的目标研究团队。