Saturday, April 20, 2024
4/20/2024
Aging-associated common human diseases such as hypertension and diabetes mellitus are influenced by small changes in multiple genetic factors, but the precise nature of each factor is still unclear. Our long-term goal is to gain deeper understanding of genetic risk factors for the common diseases by developing mouse models that closely mimic human genetic variations. ELMO1 locus, encoding engulfment and cell motility protein 1, is associated with diabetic nephropathy in humans. With a novel mouse model system, we established that the graded increase in the levels of ELMO1 determines the severity of nephropathy and cardiomyopathy in diabetic mice through increased production of reactive oxygen species (ROS). We further found that a high-dose vitamin B12, a natural superoxide scavenger, prevents and even restores the cardiac dysfunction in diabetic mice. ELMO-DOCK (dedicator of cytokinesis) complex is a guanine nucleotide exchange factor (GEF) that activates RAC (Ras-related C3 botulinum toxin substrate). Activated RAC not only triggers actin remodeling, cell growth and motility, but also is essential for the activation of NADPH oxidases, a major producer of ROS. However, why ELMO1 is so critical in diabetic complications of parenchymal cells remains unknown. Excess ROS is a common factor in aging-associated diseases, and acute tissue injuries that follow ischemia reperfusion (IR) and infection. IR induced acute kidney injury (AKI) is also preventable with B12, and our preliminary data suggest that ELMO1 is involved in determining the severity of AKI. ELMO- DOCK-RAC is evolutionally conserved as an initiator of clearing process of apoptotic cell corpse and organelle, which is in part an attempt to salvage basic elements such as nucleotides and amino acids during cell damage and apoptosis/death. Salvaging is good when these elements are scarce, but in abundance, excess ROS production only does harm. Accordingly, we propose a hypothesis that ELMO1 activates RAC in parenchymal cells responding to cellular stress and damage, and inadvertently influences the severities of disease/conditions. We will test this hypothesis with three Specific Aims; (1) to examine the effects hyperglycemia, hyperlipidemia and other factors altered by diabetes have on neonatal cardiomyocytes in culture, and the roles of ELMO1-dependent RAC1 activation in angiotensin II induced cardiac hypertrophy and failure in vivo; (2) to investigate ELMO1-dependent RAC1 activation in ischemic AKI, and its related cardiac complications, and explore the possible involvement of ELMO1 in acute respiratory distress syndrome (ARDS), the severity which is greatly enhanced by age and comorbidities in the current COVID pandemic; and (3) to determine the beneficial effects beyond superoxide scavenging which vitamin B12 execute on diabetic cardiomyopathy. Ultimately, increased understanding of factors influencing the severity of aging-associated common diseases should help lead us to a deeper knowledge of pathogenesis of these diseases and to new therapeutic strategies for patients.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
