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Principal Investigator: Benjamin P. Weaver
Organization: UT SOUTHWESTERN MEDICAL CENTER
Fiscal Year: 2024
Award: $451,000
Funding agency: National Institute on Aging
Project Summary
Compromised tissue integrity is a major cause of debility during aging. Emerging findings suggest critical
functions of lysosomes promoting tissue integrity. Our unpublished findings indicate key roles for C. elegans
PMK-1, a conserved p38 MAPK member, in promoting lysosome formation and tissue integrity during
development and aging. These non-cell autonomous functions signal between germline, epidermis and
nerve. Moreover, our data indicate that p38 MAPK acts on distinct targets in a tissue-specific and stage-
specific manner to promote lysosome function. It is not known how p38 MAPK signals between tissues to
coordinate lysosome function. We hypothesize that PMK-1 promotes lysosome function by signaling a cell
non-autonomous network regulating the regeneration and heterogeneity of lysosomes across tissues. Over
the next 2 years, the critical goals for this project are to: 1) define the PMK-1 interactome required for
lysosome regeneration, 2) reveal tissue and stage-specific functions of PMK-1 in lysosome regeneration
and heterogeneity, and 3) delineate tissue-specific contributions to PMK-1 cross-tissue signaling. We have
built an array of tools to deeply understand how p38 signaling regulates lysosome regeneration and
heterogeneity to promote tissue integrity. Our proposed interdisciplinary studies include proteomics, genetic
screens, biochemical analyses, and cell biology approaches to tackle this complex problem of
understanding non-cell autonomous p38 MAPK function. The long-term objective of the proposed studies is
to understand the molecular and physiological mechanisms of p38 MAPK signaling in tissue integrity during
development and aging.
Terms: <21+ years old><Acceleration><Adult><Adult Human><Aging><Autoregulation><Auxins><Biochemical><Biogenesis><Body Tissues><C elegans><C. elegans><C.elegans><CSAID-Binding Protein 1><CSAID-Binding Protein 2><CSBP2><Caenorhabditis elegans><Cell Body><Cell Communication and Signaling><Cell Signaling><Cell to Cell Communication and Signaling><Cell-Cell Signaling><Cells><Cellular biology><Communication><Communication Programs><Complex><Cytokine-Suppressive Antiinflammatory Drug-Binding Protein 1><Cytokine-Suppressive Antiinflammatory Drug-Binding protein 2><Data><Debility><Defect><Development><Distal><Epidermis><Epistasis><Epistatic Deviation><Event><Exhibits><Extracellular Signal-Regulated Kinase Gene><FUS-1 Protein><Fusion 1 Protein><Future><Genetic Epistasis><Genetic Screening><Germ Lines><Goals><Heterogeneity><Homeostasis><Increase lifespan><Innate Immunity><Interaction Deviation><Interdisciplinary Research><Interdisciplinary Study><Intracellular Communication and Signaling><Label><Life><Lysosomes><MAP Kinase Gene><MAPK><MAPK14><MAPK14 Mitogen-Activated Protein Kinase><MAPK14 gene><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Mediating><Metabolic><Mitogen-Activated Protein Kinase 14><Mitogen-Activated Protein Kinase Gene><Molecular><Multidisciplinary Collaboration><Multidisciplinary Research><Mxi2><Native Immunity><Natural Immunity><Natural regeneration><Nature><Nerve><Nerve Cells><Nerve Degeneration><Nerve Unit><Neural Cell><Neurocyte><Neuron Degeneration><Neurons><Non-Specific Immunity><Nonspecific Immunity><Origin of Life><PDGFA associated protein 2><Pathology><Pathway interactions><Physiologic><Physiological><Physiological Homeostasis><Post-Transcriptional Gene Silencing><Posttranscriptional Gene Silencing><Proteomics><RNA Interference><RNA Silencing><RNA interference screen><RNAi><RNAi screen><RNAi-based screen><Regeneration><Reproducibility><Role><SAPK2A><Sequence-Specific Posttranscriptional Gene Silencing><Signal Transduction><Signal Transduction Systems><Signaling><Stress><Stress-Activated Protein Kinase 2A><System><Testing><Tissues><Translating><Work><adulthood><biological signal transduction><cell biology><cellular targeting><developmental><elongating the lifespan><epistatic relationship><extend life span><extend lifespan><gain of function><gene x gene interaction><genetic epistases><in vitro Assay><intercellular communication><lifespan extension><macromolecule><member><mutant><neural degeneration><neurodegeneration><neurodegenerative><neurological degeneration><neuronal><neuronal degeneration><novel><p38><p38 MAP Kinase><p38 MAPK Gene><p38 Mitogen Activated Protein Kinase><p38 Protein Kinase><p38 SAPK><p38-Alpha><p38Alpha><pathway><programs><regenerate><scaffold><scaffolding><social role><tool>