Signal transduction in development and disease

发育和疾病中的信号转导

• 批准号: 10201946
• 负责人: RAJAT ROHATGI
• 金额: $ 78.84万
• 依托单位: STANFORD UNIVERSITY
• 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 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10201946
• 关键词: Academia; Adult; Age-Years; Area; Award; Biochemical; Biological; CRISPR/Cas technology; Cell Communication; Cell Nucleus; Cell membrane; Cell surface; Cells; Cessation of life; Cholesterol; Cilia; Collaborations; Colorectal Cancer; Complex; Congenital Abnormality; Cytoplasm; Defect; Degenerative Disorder; Development; Disease; Drug resistance; Erinaceidae; Family; Fellowship; Funding; Gene Activation; Genetic; Genetic Screening; Genetic Transcription; Glioblastoma; Goals; Human; Industry; Investigation; Laboratories; Life; Ligands; Lipid Biochemistry; Maintenance; Malignant Neoplasms; Membrane; Microscopy; Monitor; Mutation; National Institute of General Medical Sciences; Oncogenic; Organelles; Pathway interactions; Pharmaceutical Preparations; Physiological; Positioning Attribute; Proteins; Publications; Research; Research Support; Second Messenger Systems; Signal Transduction; Surface; Syndrome; System; Techniques; Therapeutic Index; Tissues; WNT Signaling Pathway; Work; base; beta catenin; ciliopathy; developmental disease; human disease; programs; receptor; repaired; resistance mechanism; smoothened signaling pathway; structural biology; transcription factor

Project Summary Signal transduction in development and disease (PI: Rohatgi) The goals of my research program are to uncover new regulatory mechanisms in cell-cell communication pathways, to understand how these mechanisms are damaged in disease states, and to devise new strategies to repair their function. Over the last 4.5 years, funding from the NIGMS has supported 23 publications across four different research areas in my laboratory: Hedgehog (Hh) signaling, WNT signaling, drug resistance mechanisms and intrinsically disordered proteins. Trainees involved in MIRA-supported research have won competitive fellowships (including a K99/R00 award from the NIGMS) and obtained independent group leader positions in both academia and industry. The next project period will tackle major unsolved problems in the vertebrate Hh and WNT signaling systems, two iconic cell-cell communication pathways that coordinate the construction of tissues during development and their subsequent maintenance throughout adult life. Despite the importance of these pathways in human diseases ranging from birth defects to cancer and degenerative conditions, many steps in Hh and WNT signaling remain poorly understood at the biochemical and cell biological level. In the Hh pathway, our focus is on understanding how a signal is detected at the cell surface and transmitted across the plasma membrane to transcriptional effectors in the cytoplasm. These signaling steps in the vertebrate Hh pathway depend on primary cilia, antenna-like organelles that project from the surfaces of most cells and are implicated in human birth defect syndromes called “ciliopathies.” Major questions under investigation include (1) how Patched 1 (PTCH1), the receptor for Hh ligands, regulates the function of Smoothened (SMO), the protein that transmits the signal across the membrane, (2) how SMO is activated at primary cilia and (3) how SMO signals to the Glioblastoma (GLI) family of transcription factors. Our MIRA- supported work has led to a new paradigm in transmembrane signaling: the use of cholesterol accessibility in the ciliary membrane as a second messenger to communicate the signal between PTCH1 and SMO. Our focus in the WNT pathway is on the multi-protein β-catenin destruction complex that suppresses WNT signaling by promoting the degradation of β-catenin. Defects in this complex drive the vast majority of colorectal cancer, a disease with an increasing burden (especially amongst people <50 years of age) predicted to cause over 1 million deaths yearly by 2030. Our emphasis is on uncovering differences in the genetic and biochemical requirements for oncogenic (mutation-driven) and physiological (ligand-driven) WNT signaling, since any successful anti-WNT drug will have to distinguish between the two to achieve an acceptable therapeutic index. Our work is supported by long-term collaborations and embraces a broad range of techniques that span structural biology, lipid biochemistry, CRISPR/Cas9-based genetic screens and microscopy. The successful completion of this project will provide a deep mechanistic understanding of these fundamental cell-cell communication systems and new strategies to monitor and modulate these pathways in human diseases.

项目摘要 发育和疾病中的信号传导（PI：Rohatgi） 我的研究项目的目标是揭示细胞间通讯的新调节机制 途径，了解这些机制如何在疾病状态下受损，并制定新的策略， 来修复它们的功能在过去的4.5年里，NIGMS的资金支持了23个出版物， 我的实验室有四个不同的研究领域：Hedgehog（Hh）信号传导，WNT信号传导，抗药性 机制和内在无序的蛋白质。参与MIRA支持的研究的受训人员赢得了 具有竞争力的奖学金（包括NIGMS的K99/R 00奖），并获得了独立的小组组长 在学术界和工业界的地位。下一个项目期间将处理 脊椎动物Hh和WNT信号系统，两个标志性的细胞间通讯途径，协调 在发育过程中组织的构建及其随后在整个成年生活中的维持。尽管 这些途径在人类疾病中的重要性，从出生缺陷到癌症和退行性疾病， 在生物化学和细胞生物学方面，Hh和WNT信号传导中的许多步骤仍然知之甚少。 水平在Hh通路中，我们的重点是了解如何在细胞表面检测到信号， 穿过质膜传递到细胞质中的转录效应子。这些信号步骤 脊椎动物Hh途径依赖于初级纤毛，从表面突出的触角样细胞器， 大多数细胞，并涉及人类出生缺陷综合征称为“纤毛病”。主要问题 研究包括（1）Hh配体的受体Patched 1（PTCH 1）如何调节 Smoothened（SMO），跨膜传递信号的蛋白质，（2）SMO如何在 初级纤毛和（3）SMO如何向成胶质细胞瘤（GLI）家族的转录因子发出信号。我们的MIRA- 支持的工作导致了跨膜信号转导的新范式：在跨膜信号转导中使用胆固醇可及性。 睫状膜作为第二信使在PTCH 1和SMO之间传递信号。我们的重点 在WNT通路中的作用是多蛋白β-连环蛋白破坏复合物，该复合物通过以下方式抑制WNT信号传导： 促进β-catenin的降解。这种复合体的缺陷导致了绝大多数结直肠癌， 疾病负担增加（特别是在50岁以下的人群中），预计会导致超过1 到2030年每年死亡100万人。我们的重点是揭示基因和生化方面的差异， 致癌（突变驱动）和生理（配体驱动）WNT信号传导的要求，因为任何 成功的抗WNT药物必须区分两者以达到可接受的治疗指数。 我们的工作得到了长期合作的支持，并采用了广泛的技术， 生物学、脂质生物化学、基于CRISPR/Cas9的遗传筛选和显微镜检查。圆满完成 这个项目将提供对这些基本的细胞-细胞通信系统的深入的机械理解 以及监测和调节人类疾病中这些途径的新策略。