Grant: Project Grant

Adult stem and progenitor cells play fundamental roles in tissue homeostasis, renewal and regeneration. When these cells become dysfunctional, these processes are negatively impacted and contribute to faster aging. My laboratory is particularly focused on one type of adult stem/progenitor cell termed a mesenchymal progenitor (MP), and their role in tissue restoration and aging. In accelerated aging conditions, such as Hutchinson Gilford Progeria Syndrome (HGPS) it has been suggested that aberrant MPs underpin this disorder, however, this hypothesis has not been directly tested. HGPS is associated with a single base mutation in the Lamin A gene, which leads to the production of an abnormal protein called progerin. Mice harboring this mutation also exhibit signs of accelerated aging. Numerous research groups have also shown that progerin accumulates in our cells during the course of normal aging. In a newly generated mouse model, we have shown that expression of progerin exclusively in MPs is sufficient to cause an accelerated aging phenotype and the resulting mice exhibit many of the symptoms observed in human HGPS. These results demonstrate that MPs play a fundamental role in aging. In this grant, we will use a variety of models to explore the cellular and molecular consequences of MP dysfunction and its impact on tissue restoration. This information will lead to a better understanding of the processes underlying normal and accelerated aging, and also provide a foundation to support therapeutic strategies aimed at improving MP function and promoting healthy aging.