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Mechanisms for GH action on epithelial cells

GH 对上皮细胞的作用机制

基本信息

批准号：
10578571
负责人：
SHLOMO MELMED
金额：
$ 36.74万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10578571
关键词：
3-Dimensional Affect Age Aging Apoptosis Attenuated CRISPR/Cas technology Cell Aging Cell Proliferation Cells Chromosomal Instability Coculture Techniques Colon DNA DNA Damage DNA Repair DNA Repair Pathway DNA-PKcs Data Devices Endocrine Epithelial Cells Epithelium Fibroblasts Gene Expression Genes Genomics Growth Growth Hormone Receptor Homeostasis Human IGF1 gene In Vitro Individual Intestines JAK2 gene Knockout Mice Left Lentivirus Malignant Neoplasms Mediating Metabolic Metabolic dysfunction Metformin Microfluidic Microchips Modeling Mus Mutation Neoplasms Nonhomologous DNA End Joining Oncogenes Organoids Pathway interactions Patients Peripheral Phenotype Phosphoric Monoester Hydrolases Phosphorylation Inhibition Pluripotent Stem Cells Proliferating Publishing Rattus Receptor Signaling Regulation Role Signal Transduction Somatotropin Somatropin Specimen TP53 gene Telomere Shortening Testing Tissue-Specific Gene Expression Tissues Transgenic Mice Transgenic Model Ultraviolet Rays aged antagonist autocrine chemotherapy cohort colon growth design ds-DNA experimental study genomic profiles homologous recombination hormonal signals hormone regulation in vivo induced pluripotent stem cell inhibitor innovation mouse model novel overexpression paracrine pegvisomant pharmacologic receptor repaired response senescence single-cell RNA sequencing stressor tissue degeneration transcriptome sequencing

项目摘要

PROJECT SUMMARY Accumulated damaged DNA, if left unrepaired, may disrupt tissue homeostasis, enabling a milieu favoring tissue degeneration, cancer, and metabolic dysfunction. DNA damage response and repair pathways are attenuated with aging and may also result in cell senescence, with senescence-associated secretory phenotype (SASP) promoting DNA damage and cell proliferation in neighboring cells, or in apoptosis. Non-pituitary growth hormone (npGH), synthesized locally in peripheral tissues, is recognized by the widely expressed GH receptor (GHR), and acts through autocrine/paracrine mechanisms. Our preliminary results show that npGH is induced by DNA damage in aged human colon tissues, in induced pluripotent stem cell (iPSC)-derived human colon 3D organoids, in hypophysectomized rat colon lacking endocrine GH, and in senescent colon cells. In turn, npGH suppresses DNA repair, further reinforcing DNA damage and resulting in chromosomal instability. We propose a novel hypothesis supporting the role of local epithelial GH as an adverse determinant of age-associated DNA damage accumulation and as a marker of epithelial aging. We will assess npGH induction and DNA damage in aged colon organoids, and Colon Intestine-Chip microfluidic devices. We will examine npGH expression in human colon tissue specimens derived from age- determined cohorts, assess spatial genomic profiles in conjunction with cells expressing npGH, and elucidate npGH as a cause of chromosomal instability. We will explore signaling mechanisms for npGH regulation of DNA damage response activity, senescence pathways, and DNA damage repair. Epithelial GHR signaling in vitro will be blocked with the GHR antagonist pegvisomant, a JAK2 inhibitor, and metformin. We will assess npGH actions in aged tissues derived from colon-specific and universal GHR knockout mice, and in GH overexpressing transgenic mice, and also assess npGH paracrine effects on colon epithelial somatic copy number alteration (sCNA) and respective genes affected by sCNA. We will study whether npGH is expressed in senescent cells, and whether it affects adjacent cell DNA damage and senescence. We will test paracrine npGH effects on senescence in Colon Intestine-Chip devices co-cultured with human colon fibroblast npGH transfectants, and will confirm in vitro results in transgenic models overexpressing GH or in GHR knockout mice. We largely focus on validated human colon epithelial models, yet experiments in this proposal are designed to elucidate a universal mechanism whereby local npGH reinforces epithelial age-associated DNA damage leading to tissue degeneration and or neoplasia.

项目总结

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

WIP1 is a novel specific target for growth hormone action.

DOI：
10.1016/j.isci.2023.108117
发表时间：
2023-11-17
期刊：
ISCIENCE
影响因子：
5.8
作者：
Apaydin, Tugce;Zonis, Svetlana;Zhou, Cuiqi;Valencia, Christian Wong;Barrett, Robert;Strous, Ger J.;Mol, Jan A.;Chesnokova, Vera;Melmed, Shlomo
通讯作者：
Melmed, Shlomo

Is GH Replacement for Adult GH Deficiency Safe?

DOI：
10.1210/clinem/dgac307
发表时间：
2022-09-28
期刊：
The Journal of clinical endocrinology and metabolism
影响因子：
0
作者：
通讯作者：

Generation of isogenic and homozygous MEN1 mutant cell lines from patient-derived iPSCs using CRISPR/Cas9.

使用 CRISPR/Cas9 从患者来源的 iPSC 中生成等基因和纯合的 MEN1 突变细胞系。

DOI：
10.1016/j.scr.2023.103124
发表时间：
2023
期刊：
Stem cell research
影响因子：
1.2
作者：
Even-Zohar,Naomi;Metin-Armagan,Derya;Ben-Shlomo,Anat;Sareen,Dhruv;Melmed,Shlomo
通讯作者：
Melmed,Shlomo

Excess growth hormone suppresses DNA damage repair in epithelial cells

DOI：
10.1172/jci.insight.125762
发表时间：
2019-02-07
期刊：
JCI INSIGHT
影响因子：
8
作者：
Chesnokova, Vera;Zonis, Svetlana;Melmed, Shlomo
通讯作者：
Melmed, Shlomo

Insulin-like Growth Factor 1 and Prolactin Levels in Chimpanzees (Pan troglodytes) Across the Lifespan.

DOI：
10.1210/jendso/bvab063
发表时间：
2021-08-01
期刊：
Journal of the Endocrine Society
影响因子：
4.1
作者：
Ben-Shlomo A;McLachlan SM;Hwe J;Aliesky H;Hasselschwert D;Mirocha J;Melmed S
通讯作者：
Melmed S