The Complement System and Cancer Cachexia
补体系统和癌症恶病质
基本信息
- 批准号:10537488
- 负责人:
- 金额:$ 47.71万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-08-01 至 2027-07-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdenocarcinomaAffectAtrophicBody Weight decreasedC3AR1 geneCachexiaCalciumCancer PatientCell NucleusCellsChimeric ProteinsCollagenComplementComplement 3aComplement 3d ReceptorsComplement 5aComplement ActivationComplement InactivatorsComplement Membrane Attack ComplexDataDepositionDevelopmentDiseaseEventFatty acid glycerol estersFoundationsFunctional disorderGoalsHealthHomeostasisImmuneImpairmentInfiltrationInflammationInjectionsKPC modelKnock-outKnowledgeLeadLectinLeukocytesLinkLiverMalignant NeoplasmsMalignant neoplasm of pancreasMediatingModelingMusMuscleMuscle CellsMuscle FibersMuscle WeaknessMuscle functionMuscular AtrophyNatural regenerationNutritional SupportOpsoninPancreasPancreatic Ductal AdenocarcinomaPathologicPathologyPathway interactionsPatientsPersonsPharmacologyPhenotypePhysical FunctionProteinsProteomicsQuality of lifeRoleSiteSkeletal MuscleSourceStimulusSyndromeTestingTherapeuticTissuesTranscriptTranslatingTumor BurdenWorkbasecancer cachexiacancer surgerycancer survivalcancer therapycell typeclinically relevantcomplement pathwaycomplement systemconventional therapyimprovedinsightmortalitymouse modelmuscle formmuscle regenerationnovelpancreatic cancer modelpancreatic cancer patientspancreatic neoplasmpreservationpreventresponseskeletal muscle wastingtherapeutically effectivetherapy developmenttranscriptome sequencingtranslational potentialtreatment strategytumortumor progression
项目摘要
Project Summary/Abstract
Cachexia is characterized by progressive skeletal muscle and body weight loss and affects up to 80% of cancer
patients. Since this loss of muscle mass contributes to weakness, reduced tolerance to conventional treatments,
and increased mortality, understanding the mechanisms that drive muscle wasting is critical to the development
of treatments to improve quality of life and enhance survival of cancer patients. However, in exploring the
mechanisms that may drive cancer-induced atrophy of myofibers, it is important to do so in the context of the
broader muscle pathologies that we and others have shown in the muscle of cachectic tumor bearing hosts,
including tissue damage, non-resolute inflammation, impaired regeneration, and increased fat, collagen and
calcium deposition. Unpublished proteomics data from our lab collected in the skeletal muscle of cachectic
pancreatic cancer patients and, subsequently, cachectic mice bearing pancreatic tumors, releaved an
enrichment of multiple pathways of the complement (Cp) system. Further immunohistochemical analyses
revealed increased deposition of the central component of the Cp system, C3, and the terminal
pathway/membrane attack complex (MAC) within muscle tissues of people and mice with pancreatic tumors,
compared to controls. Based on these findings and the established roles of Cp proteins in causing inflammation
and tissue damage, we injected mouse pancreatic cancer (KPC) cells into the pancreas of C3 knockout (C3-/-)
mice and found significant protection against KPC-induced muscle wasting and weakness, that was further linked
to reduced leukocyte infiltration into muscle and reduced fibrotic remodeling. These overall findings establish the
requirement of Cp activation for the development of cachexia, with strong translational relevance. Aim 1 will
build on these foundational findings and identify the specific Cp activation pathway and effector mechanism(s)
required for the development of tumor-induced muscle pathologies and cachexia. This will reveal optimum points
in the Cp pathway for pharmacological blockade. Aim 2 will utilize mouse Cp inhibitors that function at different
points in the Cp pathway, targeted to sites of Cp deposition, to identify the most effective therapeutic strategy to
prevent and reverse cachexia in tumor bearing mice using both the KPC model and C26 adenocarcinoma model.
Aim 3 will determine the sufficiency and requirement of local myofiber-derived C3 in pancreatic cancer-induced
immune cell infiltration into muscle, muscle damage, atrophy and weakness. This mechanistic aim is important
because the role of local myofiber-derived Cp in muscle health and disease is almost completely unknown.
Therefore, our findings here will provide mechanistic insights that will enable us to optimize and develop novel
Cp inhibitory strategies for the treatment of a broad range of muscle conditions.
项目总结/文摘
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Carl Atkinson其他文献
Carl Atkinson的其他文献
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{{ truncateString('Carl Atkinson', 18)}}的其他基金
Targeted delivery of immunosuppressive agents to the graft endothelium for the prevention of rejection in lung transplantation
将免疫抑制剂靶向递送至移植物内皮以预防肺移植中的排斥反应
- 批准号:
10481101 - 财政年份:2022
- 资助金额:
$ 47.71万 - 项目类别:
Targeted delivery of immunosuppressive agents to the graft endothelium for the prevention of rejection in lung transplantation
将免疫抑制剂靶向递送至移植物内皮以预防肺移植中的排斥反应
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10693272 - 财政年份:2022
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Complement driven innate and adaptive autoreactivity in lung transplantation
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10363208 - 财政年份:2021
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Complement driven innate and adaptive autoreactivity in lung transplantation
肺移植中补体驱动的先天性和适应性自身反应
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10228849 - 财政年份:2020
- 资助金额:
$ 47.71万 - 项目类别:
Epithelial cell complement production in the pathogenesis of chronic rhinosinusitis
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9886648 - 财政年份:2020
- 资助金额:
$ 47.71万 - 项目类别:
Brain death associated vascularized composite allograft injury and its impact on alloimmunity and functional recovery
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- 资助金额:
$ 47.71万 - 项目类别:
Epithelial cell complement production in the pathogenesis of chronic rhinosinusitis
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10355859 - 财政年份:2020
- 资助金额:
$ 47.71万 - 项目类别:
Epithelial cell complement production in the pathogenesis of chronic rhinosinusitis
慢性鼻窦炎发病机制中上皮细胞补体的产生
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10094187 - 财政年份:2020
- 资助金额:
$ 47.71万 - 项目类别:
Brain death associated vascularized composite allograft injury and its impact on alloimmunity and functional recovery
脑死亡相关血管化复合同种异体移植物损伤及其对同种免疫和功能恢复的影响
- 批准号:
10399007 - 财政年份:2020
- 资助金额:
$ 47.71万 - 项目类别:
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