Institutional Career Development Core

机构职业发展核心

• 批准号: 10705454
• 负责人: Emma Anne Meagher
• 金额: $ 17.81万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10705454
• 关键词: AKT Signaling Pathway; Affect; Ameloblasts; Award; Behavior; Behavior Disorders; Behavioral; Biological Assay; Biological Markers; Cells; Child; Collection; Complex; Creativeness; Critical Pathways; Defect; Dental Enamel; Dentistry; Development; Developmental Delay Disorders; Early identification; Enamel Formation; Enamel Organ; Encephalopathies; Epigenetic Process; Exhibits; FRAP1 gene; Face; Fetal Growth; Foundations; Future; Generations; Genes; Genetic; Grant; Heterozygote; Histology; Human; Incisor; Institution; Knock-out; Knockout Mice; Knowledge; Link; Mandible; Maturation-Stage Ameloblast; Mediating; Medicine; Membrane; Mentors; Modeling; Mus; Muscle Tonus; Mutation; National Institute of Dental and Craniofacial Research; Neurologic; Neurologic Deficit; Neurons; Neurosciences; PIK3CG gene; Pathway interactions; Patient-Focused Outcomes; Patients; Pattern; Pediatric Hospitals; Pennsylvania; Phenotype; Philadelphia; Phosphotransferases; Prevention strategy; Process; Protocols documentation; Regulation; Research; Risk Factors; Science; Series; Severities; Signal Transduction; Site; Stains; Study models; Symptoms; Syndrome; System; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Tooth Exfoliation; Tooth structure; Translational Research; Universities; Ventricular; Work; X-Ray Computed Tomography; career development; clinical application; clinically significant; craniofacial; craniofacial development; craniofacial disorder; environmental change; fascinate; in vivo; innovation; loss of function; mTOR Signaling Pathway; microCT; mineralization; mortality; mouse model; nervous system disorder; neurodevelopment; neurogenetics; neuron development; novel; single-cell RNA sequencing; tool; translational medicine; translational model; translational therapeutics; vesicle transport; white matter

ABSTRACT The proposed NIDCR KL2 application is to provide support for generating innovative translational science and questions that will lead to a mentored K series grant award. With the strong support of my mentoring team alongside robust institutional foundations from both Children’s Hospital of Philadelphia and the University of Pennsylvania Institute for Translational Medicine and Therapeutics, this project for career development will advance our scientific knowledge of craniofacial development in neuroscience and tooth mineralization. Tooth enamel and neuronal development are both highly complex and integrated systems that occur at similar time points during fetal growth. Unfortunately, many neurological disorders have limited biomarkers for identifying the presence or severity prior to preventative strategies or therapeutic interventions. Recently, evidence suggests that genetic, epigenetic, or environmental changes affecting enamel formation may reflect alterations in behavior. It is also common that among the craniofacial disorders, both neurons and ameloblasts (enamel cells) exhibit similar dysregulated patterns in vesicle transport and membrane turnover, though details of these pathways have not been well investigated. These findings, therefore, hold a fascinating promise that tooth enamel formation can be used as a biomarker for altered neurodevelopment through a common vesicle transport mechanism affecting membrane turnover in the ameloblasts and neurons. The TBC1 Domain-Containing Kinase (TBCK) syndrome is a rare craniofacial disorder that is characterized by its spectrum of neurogenetic phenotypes, ranging from developmental delay, low muscle tone, coarse facial features, and encephalopathy with altered periventricular white matter. In addition to the neurological deficits of tbck mice mimicking the human phenotypes, recent findings have demonstrated a tooth enamel phenotype in the tbck heterozygous knockout mice, indicating this mouse to be an excellent model for understanding the link between these two tissue types and enamel as a biomarker for neurologic development. We therefore propose to investigate the hypothesis that vesicle transport, specifically the PI3K-Akt signaling pathway, is disrupted in teeth (as it is in neurons), such that the tooth enamel reflects aberrant neuronal development observed in the mice and patients lacking TBCK. This hypothesis will be tested with the following specific aims: Aim 1: Characterize the tooth phenotypes of both patients and mice with deficiencies in the Tbck gene. This aim will test whether humans exhibit similar enamel phenotypes to those of tbck-/- mice. Aim 2: Determine whether aberrant vesicle transport via PI3K-Akt signaling occurs in the enamel organ of mice deficient in Tbck. This aim will test whether disrupted enamel formation is due to PI3k-Akt in the absence of tbck. Completion of this project will provide an excellent foundation for future translational work in the crossover of tooth and neurological development and will direct our understanding of the mechanistic underpinnings that drive the dynamic intracellular processes that regulate vesicle transport.

摘要 拟议的NIDCR KL 2应用程序是为产生创新的转化科学提供支持， 这些问题将导致一个指导K系列赠款奖。在我的指导团队的大力支持下 除了费城儿童医院和费城大学的强大机构基础外， 宾夕法尼亚州转化医学和治疗研究所的这个职业发展项目将 促进我们在神经科学和牙齿矿化方面对颅面发育的科学认识。 牙釉质和神经元的发育都是高度复杂和综合的系统，发生在相似的时间。 胎儿生长期间的时间点。不幸的是，许多神经系统疾病的生物标志物有限， 预防策略或治疗干预之前的存在或严重程度。最近，证据 表明影响釉质形成的遗传、表观遗传或环境变化可能反映了 在行为上。在颅面疾病中，神经元和成釉细胞（釉质）也很常见 细胞）在囊泡转运和膜周转中表现出类似的失调模式，尽管这些细节 路径还没有得到很好的研究。因此，这些发现给了我们一个令人着迷的希望， 釉质形成可以作为一种生物标志物，通过共同的囊泡运输改变神经发育 影响成釉细胞和神经元膜转换的机制。 TBC 1含结构域激酶（TBCK）综合征是一种罕见的颅面疾病，其特征在于： 它的神经发生表型谱，从发育迟缓，低肌张力，粗糙的面部， 特征和脑病伴脑室周围白色物质改变。除了神经系统的缺陷， tbck小鼠模仿人类表型，最近的研究结果表明， tbck杂合基因敲除小鼠，表明该小鼠是理解 这两种组织类型和釉质之间的差异，作为神经发育的生物标志物。因此我们建议 为了研究囊泡转运，特别是PI 3 K-Akt信号通路，被破坏的假设， 牙齿（因为它是在神经元），这样牙釉质反映了异常的神经元发育中观察到的。 缺乏TBCK的小鼠和患者。将以下列具体目标检验这一假设： 目的1：表征Tbck基因缺陷的患者和小鼠的牙齿表型。 这一目标将测试人类是否表现出与tbck-/-小鼠相似的釉质表型。目标2：确定 通过PI 3 K-Akt信号传导的异常囊泡转运是否发生在缺乏PI 3 K-Akt的小鼠的釉质器官中， 在Tbck。该目的将测试在不存在tbck的情况下破坏的釉质形成是否是由于PI 3 k-Akt。 该项目的完成将为未来的翻译工作提供一个良好的基础， 牙齿和神经系统的发展，并将指导我们的机械基础的理解，驱动 调节囊泡运输的动态细胞内过程。

项目成果

Effector memory CD8 T-cells as a novel peripheral blood biomarker for activated T-cell pediatric acute liver failure.

• DOI: 10.1371/journal.pone.0286394
• 发表时间: 2023
• 期刊: PloS one
• 影响因子: 3.7

Invasive Aspergillosis Causing Aortic Pseudoaneurysm and Endocarditis After Heart Transplantation.

• DOI: 10.1161/circimaging.120.012370
• 发表时间: 2021-06
• 期刊: Circulation. Cardiovascular imaging
• 作者: Reza N;Genuardi MV;Weikert BC;McLean R;Deshpande C;Jagasia D;Tiku Owens A
• 通讯作者: Tiku Owens A

Adequate Decongestion Is Still the Question in Heart Failure.

足够的解答仍然是心力衰竭的问题。

• DOI: 10.1159/000511413
• 发表时间: 2021
• 期刊: Cardiology
• 影响因子: 1.9
• 作者: Reza N;Zieroth S
• 通讯作者: Zieroth S

Natural history of multiple sulfatase deficiency: Retrospective phenotyping and functional variant analysis to characterize an ultra-rare disease.

• DOI: 10.1002/jimd.12298
• 发表时间: 2020-11
• 期刊: Journal of inherited metabolic disease
• 影响因子: 4.2
• 作者: Adang LA;Schlotawa L;Groeschel S;Kehrer C;Harzer K;Staretz-Chacham O;Silva TO;Schwartz IVD;Gärtner J;De Castro M;Costin C;Montgomery EF;Dierks T;Radhakrishnan K;Ahrens-Nicklas RC
• 通讯作者: Ahrens-Nicklas RC

Body mass index increase in preschoolers with heterogeneous psychiatric diagnoses treated with risperidone.

• DOI: 10.1177/02698811211008592
• 发表时间: 2021-09
• 期刊: JOURNAL OF PSYCHOPHARMACOLOGY
• 影响因子: 4.1
• 作者: Avrahami, Matan;Peskin, Miriam;Moore, Tyler;Drapisz, Adi;Taylor, Jerome;Segal-Gavish, Hadar;Balan-Moshe, Livia;Shachar, Issac;Levy, Tomer;Weizman, Abraham;Barzilay, Ran
• 通讯作者: Barzilay, Ran