Senescent Cell Transplantation Model

Project: Research project

Project Details


DESCRIPTION (provided by applicant): Aging is the biggest risk factor for most of the chronic diseases that account for the bulk of morbidity, mortality, and health expenditures in the US. A key mechanism that likely contributes to both age-related dysfunction and these chronic diseases is cellular senescence. Our goal is to devise interventions based on targeting senescent cells to ameliorate age-related chronic diseases as a group. To do so, model systems that are tractable to manipulation are needed to discover effects of targeting senescent cells on dysfunction. Our hypothesis is that transplanting senescent cells will induce adverse aging-like phenotypes that non- senescent cells will not. We found that transplanting senescent fat cell progenitors -preadipocytes- into rodents caused sustained glucose intolerance and cardiac dysfunction, while non-senescent cells did not. We propose developing a model that could accelerate senolytic drug development and understanding about cellular senescence. Aim 1 is to optimize and characterize the senescent cell transplantation model. We will: 1) determine the relation between transplanted senescent cell numbers and extent of resulting metabolic and cardiovascular dysfunction, 2) compare effects of transplanting cells in which senescence has been caused by different inducers (drugs, radiation, metabolites), 3) determine how long transplanted senescent cells survive, 4) track where transplanted senescent cells go, 5) examine effects of transplanting senescent cells into different sites in recipients, and 6) test if transplanting replication- or radiation-induced senescent human cells into immunodeficient rodents is a viable model. Aim 2 is to develop methods for manipulating pathways in transplanted senescent cells so mechanisms through which senescent cells cause dysfunction can be elucidated. To test if eliminating transplanted senescent cells alleviates glucose intolerance and cardiovascular dysfunction, preadipocytes to be transplanted will be transduced with a lentivirus comprising a constitutive promoter driving a drug-inducible suicide gene -ATTAC- and green fluorescence protein. The drug, AP20187, which activates the suicide gene, will have little effect on the recipients' own cells. By administering AP20187 to animals that have been transplanted with these transduced cells, we will be able to test epistatically if eliminating these cells reverses senescence-associated metabolic and cardiovascular dysfunction. We will use a similar transduction approach to express shRNA's in transplanted senescent cells in order to manipulate expression of key genes involved in the genesis of the SASP. Our overall goal is to devise clinical interventions to remove senescent cells or ameliorate the SASP in non-genetically modified individuals. The transplanted senescent cell model will be highly useful in: 1) dissecting the role of cellular senescence in the genesis and progression of age-related dysfunction, 2) testing effects of varying senescent cell burden, 3) identifying pathways in senescent cells that are responsible for adverse phenotypes, and 4) developing and testing pharmacological interventions for eliminating senescent cells or preventing their effects.
StatusNot started


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