Structure-function analysis of Mullerian Inhibiting Substance (MIS)

苗勒管抑制物质（MIS）的结构-功能分析

基本信息

批准号：
10665653
负责人：
THOMAS B THOMPSON
金额：
$ 38.94万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-18 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10665653
关键词：
Adopted Adult Affinity Agonist Anti-Mullerian Hormone Receptor Type II Binding Biochemical Biological Biological Assay Biological Markers Biological Models Biology Biophysics Cell Culture Techniques Cells Cervix Uteri Complex Data Development Embryonic Development Engineering Extracellular Domain Family Female Fertility Fetus Future Generations Hand Human In Vitro Laboratories Ligand Binding Ligand Binding Domain Ligands Male Genital Organs Mammalian Oviducts Measures Membrane Proteins Modeling Molecular Mullerian-inhibiting substance receptor Mutation Nature Ovarian Ovarian Ablation Ovary Phosphorylation Phosphotransferases Play Polycystic Ovary Syndrome Production Public Health Reagent Receptor Signaling Recombinant Proteins Reproducibility Reproduction Reproductive Biology Research Personnel Roentgen Rays Role Serum Sex Differentiation Signal Transduction Signaling Protein Specificity Structure Structure of paramesonephric duct Subcellular structure Surface Plasmon Resonance Syndrome Testing Transforming Growth Factor beta Transforming Growth Factor beta Receptors Urogenital ridge structure Uterus Woman Work X-Ray Crystallography analog antagonist bone morphogenetic protein receptor type I chemotherapy extracellular female reproductive system folliculogenesis granulosa cell human female in vivo insight male member mullerian-inhibiting hormone novel novel therapeutics ovarian reserve primary ovarian insufficiency rational design receptor reproductive reproductive system disorder small molecule structural biology substance use

项目摘要

Project Summary: Müllerian Inhibiting Substance (MIS) or Anti- Müllerian Hormone (AMH), originally identified for its role in male sex differentiation during development, has emerged as a significant molecule in female reproduction. For example, MIS plays an important role in regulating follicle development and serum levels and is now used as a measure of ovarian reserve. Mutations in MIS are associated with both male and female reproductive disorders, including Persistent Müllerian Duct Syndrome (PMDS) in males and Polycystic Ovary Syndrome (PCOS) in females. As a member of the TGFβ family, MIS signals through a type I and type II receptor. Uniquely, MIS signals through its own type II receptor MISRII and the type I receptor Alk2, which is utilized by multiple ligands. While previous studies have detailed TGFβ family ligand interactions, how MIS interacts, at the molecular level, with MISRII and Alk2 is unknown. The objective of this proposal is to understand how MIS interacts with its cognate receptors and how specific MIS signaling is generated through these receptors. Here, we will combine both structural and functional approaches, including X-ray crystallography, cell-based signaling assays, structure-based engineering, and biological models of fertility and ovarian protection. We will pursue the following three specific aims (1) determine the crystal structure of MIS with MISRII and Alk2, (2) characterize the MIS receptors and determine how the generate MIS-specific signaling, using both the extracellular and intercellular domains and (3) generate MIS analogs that will be tested in both in vitro binding and cell-based assays, along with in vivo assay including an AAV9 model of follicle suppression. Collectively, this proposal will uncover how MIS interacts with its receptors providing a platform for developing reagents that modify MIS activity with the potential for future application in reproductive therapies.

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Structural Basis of Non-Latent Signaling by the Anti-Müllerian Hormone Procomplex.

抗苗勒管激素原复合物非潜在信号传导的结构基础。

DOI：
10.1101/2024.04.01.587627
发表时间：
2024
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Howard,JamesA;Hok,Lucija;Cate,RichardL;Sanford,NathanielJ;Hart,KaitlinN;Leach,EdmundAe;Bruening,AlenaS;Pépin,David;Donahoe,PatriciaK;Thompson,ThomasB
通讯作者：
Thompson,ThomasB