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Assessing the mechanisms directing cell fate in the dorsal spinal cord

评估背侧脊髓细胞命运的机制

基本信息

批准号：
10615870
负责人：
SAMANTHA J BUTLER
金额：
$ 45.09万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10615870
关键词：
Address Adopted Aftercare BMP4 Bone Morphogenetic Proteins Cell model Cells ChIP-seq Chicken Model Chickens Complex Data Development Developmental Biology Disease Dorsal Drug Modulation Drug Screening ES Cell Line Environment Family Family member Gene Expression Profiling Genetic Transcription Germ Cells Growth Factor In Vitro Individual Injury Interneurons Ligands Light Logic Mediating Medical Modality Modeling Mus Nature Nociception Outcome Pain Paralysed Pathway interactions Patients Pattern Peripheral Pluripotent Stem Cells Population Process Production Proliferating Proprioception Protein Family Protocols documentation Pruritus Reaction Research Resolution Role SHH gene Second Messenger Systems Sensory Series Signal Pathway Signal Transduction Signaling Protein Specific qualifier value Spinal Spinal Cord Spinal cord damage Subgroup System Touch sensation Translating Tretinoin Vertebral column WNT Signaling Pathway Well in self bone morphogenetic protein receptor type I cell type design differentiation protocol drug testing embryonic stem cell in vivo knock-down member morphogens motor control mouse model nerve stem cell neural progenitor receptor repaired response small molecule inhibitor somatosensory stem cell differentiation stem cell model transcription factor transcriptome transcriptomics

项目摘要

Project Summary The somatosensory system permits us to perceive and react to the environment through modalities that include touch, nociception, thermosensation and proprioception. Somatosensory information is received peripherally and then relayed centrally by different populations of dorsal interneurons (dIs; dI1-dI6) in the spinal cord. Our research objectives are to understand the mechanisms that establish dIs during development and then apply these principles towards designing differentiation protocols to direct the formation of specific populations of dIs from pluripotent stem cells. These cells have the potential to repair damaged sensory circuits and act as substrates for drug screening platforms. We have focused on dissecting the role of the bone morphogenetic protein (BMP) family in dI fate specification. BMPs were widely assumed to act as morphogens, patterning the dorsal spinal cord in a concentration-dependent mechanism similar to the manner in which sonic hedgehog (Shh) patterns the ventral spinal cord. However, our recent studies using mouse, chicken, and mouse embryonic stem cell (mESC) models have found that no evidence that BMPs act as morphogens. Rather, BMPs have signal-specific activities, with differential abilities to direct dorsal progenitor (dP) patterning and/or differentiation through specific type I BMP receptors. Our recent in vivo and in vitro studies have also suggested that dI fates are established in a series of nested choice points. In our model, spinal progenitors are dorsalized by retinoic acid (RA), subdivided into multipotential dP subgroups by BMP signaling, and then resolve into specific dI fates. Since little is known about this patterning process, we will assess in Aim 1 how multipotential dP fates are first established by RA and BMP signaling and identify the mechanisms directing multipotential dPs into specific dI identities. In Aim 2, we will determine the nature of the intracellular response that permits specific BMPs to drive dPs towards different dI identities, addressing two unresolved questions: [1] are canonical receptor regulated (R)-Smads activated in a BMP-specific manner to result in distinct patterning activities? And [2] what factors do the R-Smads in turn regulate to promote dI fates? Together, these studies will investigate a long-standing problem in developmental biology, i.e., understanding how specific outcomes arise from a common signal, and shed light on the specification of dIs, cell types needed to permit paralyzed patients to again interpret their sensory environment. Our specific aims are as follows: Aim 1: Identify the mechanism(s) that establish multipotential dPs and assign them into individual dI fates. Hypothesis: RA±BMP4 direct the formation of multipotential dP subgroups, which resolve into specific dI fates by the asymmetric activation of additional endogenous signaling pathways, such as the Wnt pathway. Aim 2: Assess the role of the Smad and Id families in BMP-induced dI fate specification. Hypothesis: BMPs differentially activate Smad1 and/or Smad5, to regulate the activity of Id family members.

项目总结