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Novel Mechanisms of Regenerative Tissue Repair

再生组织修复的新机制

基本信息

批准号：
10807556
负责人：
Sundeep G Keswani
金额：
$ 1.22万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10807556
关键词：
Address Adoptive Transfer Adult Affect CD4 Positive T Lymphocytes CD44 gene Cells Cicatrix Data Dermal Economic Burden Engineering Extracellular Matrix FOXP3 gene Fibroblasts Fibrosis Goals Health Healthcare Human Hyaluronan Hydrogels Immunity In Vitro Inflammation Injury Interleukin-10 Interleukin-4 Knowledge Lymphocyte Subset Mediating Mediator Mission Molecular Molecular Weight Mus Outcome Patients Phase Phenotype Physiology Production Reporter Reporting Research Risk Severe Combined Immunodeficiency Signal Transduction Skin injury System T-Lymphocyte T-Lymphocyte Subsets Testing Wound models angiogenesis antifibrotic treatment design fetal healing in vivo mouse model neovascularization novel postnatal pre-clinical prevent psychosocial reconstitution regenerative regenerative tissue response to injury skin wound therapeutically effective tissue repair wound wound healing

项目摘要

PROJECT SUMMARY Postnatal dermal injuries heal with scars, resulting in major health, psychosocial and economic burdens. Our team has studied the mechanisms of fetal regenerative tissue repair with the ultimate goal to develop anti- fibrotic therapies. In pursuit of this mission and with previous R01 support, our team has (i) found that IL-10 is a key regulator of fetal wound repair and promotes scarless healing, (ii) replicated the fetal scarless phenotype by application of IL-10 on postnatal dermal wounds, (iii) revealed new mechanisms that control extracellular matrix (ECM) remodeling and neovascularization via high molecular weight hyaluronan (HMW-HA) signaling, (iv) demonstrated that HMW-HA drives T lymphocyte-mediated IL-10 expression, (v) recently reported a temporal influx of predominantly CD4+ T lymphocytes in murine skin wounds that correlated with the proliferative and remodeling phases of wound healing, and (vi) obtained evidence that reconstitution of immunity by adoptive transfer of functional CD4+ T lymphocytes in severe combined immune deficient mice significantly reduced inflammation, decreased fibrosis, and healed post-injury dermal wounds with less scarring. While our collective data strongly suggest a concerted HMW-HA-mediated IL-10-dependent crosstalk between fibroblast cells and mobilized T lymphocytes in response to injury, little is known about the identity of IL-10-producing CD4+ T lymphocyte subsets and how they contribute to dermal wound repair outcomes. We hypothesize that: (a) CD4+ lymphocyte subsets differentially regulate postnatal dermal scarring via IL-10- dependent signaling and (b) HA and the hyaladherins transduce signals to drive IL-10 production by CD4+ lymphocytes, which reduces scarring risks. To obtain experimental evidence that supports our hypothesis and provides compelling clues to design effective anti-scar therapies, we propose three specific aims. In aim 1, we will identify the mechanisms by which IL-10-producing CD4+ T lymphocyte subsets regulate inflammation, ECM formation and angiogenesis to reduce scar formation in vitro and in vivo. In this and subsequent aims, we will use unique 10Bit4 mouse models engineered with a triple reporter system - IL-4 (RFP), Il-10 (CD90.1), and Foxp3 (GFP) - to unambiguously assess the requirement of different T lymphocyte subsets presumed to transduce anti-scar functions. In aim 2, we will investigate how HA regulates CD4+ lymphocyte production of IL-10 via CD44 signaling, and determine how HA-stabilizing hyaladherins influence this signaling cascade. Finally in aim 3, we will determine if HA-mediated endogenous IL-10 production can direct adult fibroblasts toward a fetal-like regenerative phenotype and if this signaling can influence human scarring phenotypes. Using our gained knowledge, we will then optimize a translational HMW-HA-based hydrogel treatment system to promote stable IL-10 production by CD4+ lymphocytes in dermal wounds and test its effects on scarring outcomes in a preclinical wound healing model. Overall, the proposed aims will reveal new CD4+ lymphocyte physiology in wound healing and lead to a novel translational treatment paradigm to mitigate dermal scarring.

项目总结

项目成果

期刊论文数量（19）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Endogenous Interleukin-10 Contributes to Wound Healing and Regulates Tissue Repair.

内源性 IL-10 有助于伤口愈合并调节组织修复。

DOI：
10.1016/j.jss.2022.12.004
发表时间：
2023
期刊：
The Journal of surgical research
影响因子：
0
作者：
Short,WalkerD;Rae,Meredith;Lu,Thomas;Padon,Benjamin;Prajapati,TanujJ;Faruk,Fayiz;Olutoye2nd,OluyinkaO;Yu,Ling;Bollyky,Paul;Keswani,SundeepG;Balaji,Swathi
通讯作者：
Balaji,Swathi

IL-10 promotes endothelial progenitor cell infiltration and wound healing via STAT3.

DOI：
10.1096/fj.201901024rr
发表时间：
2022-07
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
0
作者：
通讯作者：

Skin-specific knockdown of hyaluronan in mice by an optimized topical 4-methylumbelliferone formulation.

DOI：
10.1080/10717544.2021.1886376
发表时间：
2021-12
期刊：
Drug delivery
影响因子：
6
作者：
Steen EH;Short WD;Li H;Parikh UM;Blum A;Templeman N;Nagy N;Bollyky PL;Keswani SG;Balaji S
通讯作者：
Balaji S

Ancillary documents for NIH grant applications: The pages beyond the science.

NIH 资助申请的辅助文件：科学之外的页面。

DOI：
10.1016/j.surg.2022.09.038
发表时间：
2023
期刊：
Surgery
影响因子：
3.8
作者：
Fahrenholz,Monica;Cheng,LilyS;Olutoye2nd,Oluyinka;Degala,AnjaliA;Keswani,SonyaS;Lee,Taylor;Goldstein,AllanM;Keswani,SundeepG
通讯作者：
Keswani,SundeepG

Hyaluronidases in Human Diseases.