Computer simulations of lysosomal and osteoclast microphysiology

溶酶体和破骨细胞微生理学的计算机模拟

基本信息

批准号：
8793360
负责人：
Michael Grabe
金额：
$ 17.99万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8793360
关键词：
Computer simulations lysosomal osteoclast microphysiology

项目摘要

DESCRIPTION (provided by applicant): The ability of cells to create and tightly regulate the chemical environment in specialized compartments is critical to many fundamental biological processes. Lysosomes and the extracellular compartment (ECC) of bone resorbing osteoclasts must maintain an acidic interior pH, around 4.5, to effectively destroy macromolecules and bone matrix, respectively. These cellular compartments are intimately linked, since the ECC is derived from lysosomes; and they both use a common set of membrane proteins to achieve a low lumenal pH. Dysfunction in the acidification process in lysosomes can lead to lysosomal storage diseases; and aberrant bone resorption by osteoclasts is associated with a number of bone diseases including osteoporosis, which affects 10 million people in the United States and causes significant morbidity and mortality. Despite the profound influence that the proper functioning of osteoclasts and lysosomes has on human health, there is no unified understanding of how pH is regulated in these systems. In recent years, there has been a dramatic increase in our knowledge of the proteins involved in acidification of lysosomes and ECC and their biophysical properties. Several critical proteins in this process include the V-ATPase proton pump, ClC-7 chloride antiporter, and the proton leak channel. The goal of this proposal is to create comprehensive mathematical models of pH regulation in lysosomes (Aim 1) and the ECC of osteoclasts (Aim 2). We will start by individually calibrating the ionic flux of each relevant transporter and ion channel over a large range of environmental conditions. These performance surfaces will then be used as inputs in the construction of ordinary differential equation (ODE) based models of ion regulation in lysosomes and the ECC. The ODE models will be calibrated against experimental data. We will also create 3D models of both cellular compartments, and carry out acidification studies using Monte Carlo simulations. We expect that our studies will help resolve a controversy in the field regarding the identity of the counter-ion flux required for proton pumping, and the models will guide new experiments. Additionally, our models will reveal potential drug targets for inhibiting ECC acidification that could lead to new osteoporosis treatments.

描述（由申请人提供）：细胞在专门隔室中创建和严格调节化学环境的能力对于许多基本生物过程至关重要。溶酶体和骨吸收破骨细胞的细胞外区室 (ECC) 必须维持酸性内部 pH 值（约 4.5），才能分别有效地破坏大分子和骨基质。这些细胞区室紧密相连，因为 ECC 源自溶酶体；它们都使用一组通用的膜蛋白来实现低腔内 pH 值。溶酶体酸化过程的功能障碍可导致溶酶体贮积病；破骨细胞的异常骨吸收与许多骨疾病有关，其中包括骨质疏松症，它影响着美国的 1000 万人，并导致显着的发病率和死亡率。尽管破骨细胞和溶酶体的正常功能对人类健康有着深远的影响，但对于这些系统中 pH 值的调节机制还没有统一的认识。近年来，我们对参与溶酶体和 ECC 酸化的蛋白质及其生物物理特性的了解急剧增加。该过程中的几个关键蛋白质包括 V-ATP 酶质子泵、ClC-7 氯化物逆向转运蛋白和质子泄漏通道。该提案的目标是创建溶酶体 pH 调节（目标 1）和破骨细胞 ECC（目标 2）的综合数学模型。我们将首先在大范围的环境条件下单独校准每个相关转运体和离子通道的离子通量。然后，这些性能曲面将用作构建基于常微分方程 (ODE) 的溶酶体和 ECC 离子调节模型的输入。 ODE 模型将根据实验数据进行校准。我们还将创建两个细胞区室的 3D 模型，并使用蒙特卡罗模拟进行酸化研究。我们希望我们的研究将有助于解决该领域关于质子泵浦所需的反离子通量的争议，并且这些模型将指导新的实验。此外，我们的模型将揭示抑制 ECC 酸化的潜在药物靶点，从而可能导致新的骨质疏松症治疗。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A mathematical model of osteoclast acidification during bone resorption.

DOI：
10.1016/j.bone.2016.09.007
发表时间：
2016-12
期刊：
BONE
影响因子：
4.1
作者：
Marcoline, Frank V.;Ishida, Yoichi;Mindell, Joseph A.;Nayak, Smita;Grabe, Michael
通讯作者：
Grabe, Michael

Protons in small spaces: Discrete simulations of vesicle acidification.

小空间中的质子：囊泡酸化的离散模拟。

DOI：
10.1371/journal.pcbi.1007539
发表时间：
2019
期刊：
PLoS computational biology
影响因子：
4.3
作者：
Singh,Apeksha;Marcoline,FrankV;Veshaguri,Salome;Kao,AimeeW;Bruchez,Marcel;Mindell,JosephA;Stamou,Dimitrios;Grabe,Michael
通讯作者：
Grabe,Michael

A model of lysosomal pH regulation.

DOI：
10.1085/jgp.201210930
发表时间：
2013-06
期刊：
The Journal of general physiology
影响因子：
0
作者：
Ishida Y;Nayak S;Mindell JA;Grabe M
通讯作者：
Grabe M

Direct observation of proton pumping by a eukaryotic P-type ATPase.

DOI：
10.1126/science.aad6429
发表时间：
2016-03-25
期刊：
Science (New York, N.Y.)
影响因子：
0
作者：
Veshaguri S;Christensen SM;Kemmer GC;Ghale G;Møller MP;Lohr C;Christensen AL;Justesen BH;Jørgensen IL;Schiller J;Hatzakis NS;Grabe M;Pomorski TG;Stamou D
通讯作者：
Stamou D