2021 |
Hansen, Malene |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Role of Selective Autophagy in Organismal Health @ Buck Institute For Research On Aging
PROJECT SUMMARY Autophagy is a cellular, homeostatic process with important roles in aging and age-related diseases. During autophagy, cytosolic material or cargo is sequestered into autophagic vesicles called autophagosomes for subsequent lysosomal degradation; however, the underlying mechanisms for how the turover of specific types of cargo, e.g., protein aggregates or mitochondria, collectively referred to as selective autophagy, contributes to cellular proteostasis and organismal health remain elusive. We and others recently showed a conserved role for the first identified autophagy cargo receptor in metazoans, p62/SQSTM1 in mediating proteostasis and organismal benefits in an autophagy-dependent manner. In particular, we showed that p62 overexpression in the short-lived nematode C. elegans is sufficient to induce autophagy and extend life- and healthspan, and protect against protein aggregation predominantly in neurons. Moreover, p62 is selectively required for the beneficial effects of a hormetic heat shock, a conserved longevity regimen that we previously showed to induce autophagy. Collectively, these studies suggest the hypothesis that p62 plays an instructive role in inducing tissue-specific, selective autophagy to facilitate organismal benefits. This is a novel concept because autophagy receptors are traditionally viewed as factors facilitating cargo sequestration, rather than being active inducers of this complex, multi-step turnover process. We propose to address this hypothesis by using C. elegans to investigate the molecular mechanisms by which a hormetic heat shock via p62 or direct p62 overexpression regulate autophagy cell autonomously and improve organismal health via cell non-autonomous effects. Specifically, in Aim 1, we will use genetic approaches to test how a hormetic heat shock engages p62 to regulate autophagy especially in neurons. In Aim 2, we will investigate the cell-autonomous and cell non-autonomous mechanisms by which p62 induce autophagy and improve fitness. Finally, in Aim 3, we will use genetic and biochemical approaches to identify new p62-relevant cargo and p62-like receptors engaged by hormetic heat shock. These studies are significant because they will advance our knowledge of how selective autophagy contributes to organismal healthspan. These studies are innovative because they use a powerful combination of techniques and models to investigate the novel regulatory concept in the autophagy field that an autophagy receptor is sufficient to induce beneficial autophagy, potentially via cell non-autonomous mechanisms. Since autophagy plays critical roles in many human age-related disorders, understanding the regulation of autophagy and the conserved mechanisms by which autophagy affect aging in multicellular organisms like C. elegans are likely to provide new important insights relevant to aging, which also may help develop treatments for age-related diseases.
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0.951 |
2021 |
Hansen, Malene |
P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. |
San Diego Nathan Shock Center @ Salk Institute For Biological Studies
PROJECT SUMMARY ? Research Development Core The SD-NSC Research Development Core (ResDev Core) will provide support for career development of junior researchers entering the field of basic aging biology, as well as established investigators who wish to join the field of aging research. Specifically, the ResDev Core will support the scientific goals of SD-NSC to enhance the understanding of the role of cell heterogeneity in the aging process by promoting career development of aging researchers in three different ways: 1) by providing seed funding for projects interested in taking advantage of the unique scientific services offered by the SD-NSC Research Resource Cores (Human Cell Models of Aging Core, Heterogeneity of Aging Core, and Integrative Models of Aging Core), 2) by providing conceptual and practical training in the scientific services covered by the three Research Resource Cores, and 3) by establishing a personalized mentoring program between junior and senior members of the NSC network and beyond. The ResDev Core will be led by Dr. Malene Hansen, Sanford Burnham Prebys Medical Discovery Institute (SBP), who brings local, national, and international aging research knowledge, and extensive expertise and high motivation in mentoring junior scientists. The approach will capitalize on a highly integrative and innovative approach by providing conceptual and practical training in the scientific Cores along with formalized mentoring in grant writing and career development. First, a two-track pilot grant program will be launched in which applicants apply for funding for Core usage and mentoring, either directly from submitted applications or via a grant-writing support program. Second, a one-day workshop to provide training in the scientific Cores will take place the day after the yearly La Jolla Aging Meeting, a free one-day aging symposium at the Salk Institute for Biological Studies (Salk) in San Diego organized by researchers at Salk and SBP. This workshop will feature modules on the techniques and analyses provided by the three scientific cores, along with information about potential career tracks in scientific Core services. In addition, a module on grant writing will be offered. Third and finally, a two-track personalized mentoring program will be established in which junior researchers will be mentored by established investigators, either as part of the pilot grant program or via pairing of mentee-mentor relationships formed at national NSC meetings, and beyond.
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0.934 |