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PID2021-127227OB-I00

Financiado

HYPOXIC REGULATION OF THE SENESCENT SECRETOME IN AGE-RELATED PATHOLOGIES

RESEARCH OVER THE LAST DECADE HAS CONVINCINGLY EVIDENCED THAT CELLULAR SENESCENCE AND LOW OXYGEN (O2) AVAILABILITY (HYPOXIA) ARE DISTINCTIVE FEATURES INVOLVED IN THE PHYSIOPATHOLOGY OF AGE-ASSOCIATED DISORDERS INCLUDING LUNG CANCE... ver más

01/01/2021

157K€

Presupuesto del proyecto: 157K€

Líder del proyecto

UNIVERSIDAD DE SEVILLA No se ha especificado una descripción o un objeto social para esta compañía.

Total investigadores 3667

Financiación concedida El organismo AGENCIA ESTATAL DE INVESTIGACIÓN notifico la concesión del proyecto el día 2021-01-01 No tenemos la información de la convocatoria

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Líder del proyecto

UNIVERSIDAD DE SEVILLA No se ha especificado una descripción o un objeto social para esta compañía.

Total investigadores 3667

Presupuesto del proyecto 157K€

Descripción del proyecto RESEARCH OVER THE LAST DECADE HAS CONVINCINGLY EVIDENCED THAT CELLULAR SENESCENCE AND LOW OXYGEN (O2) AVAILABILITY (HYPOXIA) ARE DISTINCTIVE FEATURES INVOLVED IN THE PHYSIOPATHOLOGY OF AGE-ASSOCIATED DISORDERS INCLUDING LUNG CANCER AND PULMONARY FIBROSIS. CELLULAR SENESCENCE IS CHARACTERISED BY A PERMANENT AND IRREVERSIBLE CELL CYCLE ARREST AND THE ACQUISITION OF AN INTENSE SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE (SASP). MOUNTING EVIDENCE HAS SHOWN THAT THE SASP ACCOUNTS FOR MOST OF THE PARACRINE EFFECTS OF CELLULAR SENESCENCE BOTH IN NORMAL PHYSIOLOGY AND UNDER PATHOLOGICAL CONDITIONS. THEREFORE, UNDERSTANDING THE MECHANISMS THAT MODULATE THE COMPOSITION AND INTENSITY OF THE SASP IS A FUNDAMENTAL BIOLOGICAL QUESTION WITH SIGNIFICANT TRANSLATIONAL IMPLICATIONS IN AGE-ASSOCIATED DISORDERS. SENESCENT CELLS ACCUMULATE IN SOLID TUMOURS OR IN FIBROTIC AREAS WHERE OXYGEN AVAILABILITY IS VERY LIMITED. TO LIVE UNDER THESE CONDITIONS, SENESCENT CELLS MUST RESPOND AND ADAPT TO HYPOXIA VIA THE STABILIZATION OF HYPOXIA-INDUCIBLE TRANSCRIPTION FACTORS, HIF-1 AND HIF-2. HIFS UPREGULATE A PLETHORA OF TARGET GENES INCLUDING NF-KB, A CHIEF FACTOR IN CONTROLLING THE COMPOSITION OF THE SASP. I HYPOTHESISE THAT LOCAL HYPOXIA OF THE CELLULAR MICROENVIRONMENT DETERMINES THE COMPOSITION AND INTENSITY OF THE SASP IN AGE-RELATED DISORDERS, A CONCEPT THAT I WILL NAME HSASP. GIVEN THE INTRINSIC HETEROGENEITY OF THE SASP ACROSS TISSUES, I WILL TEST THIS HYPOTHESIS IN LUNG CANCER AND PULMONARY FIBROSIS MODELS WHERE THERE IS A CONCOMITANT ACCUMULATION OF SENESCENT CELLS IN HYPOXIC AREAS. I WILL USE A VARIETY OF GENOTOXIC AGENTS TO INDUCE CELLULAR SENESCENCE IN LUNG CANCER AND STROMAL CELLS EXPOSED TO A DECREASING RANGE OF O2 TENSIONS. I WILL ELUCIDATE THE ROLE OF HIF-1A AND HIF-2A SUBUNITS IN SENESCENT CELLS AND THEIR IMPACT ON THE PROGRESSION OF LUNG CANCER AND PULMONARY FIBROSIS. FINALLY, I WILL IDENTIFY PHYSIOLOGICALLY RELEVANT HSASP FACTORS AND DEFINE THEIR FUNCTIONAL EFFECTS ON IN CELLULO AND IN VIVO MODELS OF LUNG CANCER AND LUNG FIBROSIS.PROMISING THERAPEUTIC OPPORTUNITIES HAVE EMERGED TO ELIMINATE SENESCENT CELLS (SENOTHERAPIES) IN AGE-RELATED DISORDERS. HOWEVER, THE CLINICAL TRANSLATION OF THESE SENOTHERAPIES IS YET CHALLENGING AS THEY USUALLY HAVE ASSOCIATED UNSPECIFIC EFFECTS ON NORMAL CELL PHYSIOLOGY. HENCE, THERE IS A NEED FOR NOVEL THERAPIES THAT SPECIFICALLY ATTENUATE THE ADVERSE EFFECTS OF THOSE SASP FACTORS INVOLVED IN TISSUE DYSFUNCTION WHILE MAINTAINING THE BENEFICIAL EFFECTS OF CELLULAR SENESCENCE IN TISSUE HOMEOSTASIS. THE PROPOSED RESEARCH AIMS AT IDENTIFYING THESE PHYSIOLOGICALLY RELEVANT HSASP FACTORS AND THE MECHANISMS BY WHICH CONTRIBUTE TO THE PROGRESSION OF LUNG CANCER AND PULMONARY FIBROSIS. YPOXIA\FIBROSIS\CANCER\HIF\AGEING\SENESCENCE

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