Although enhanced disease risk in the Down Syndrome (DS) population is ultimately caused by trisomy of chromosome 21 (T21), the likelihood of someone with DS getting any particular disease and the severity of symptoms are highly variable. In this proposal we will test the hypothesis that deficiencies in macroautophagy (autophagy) drive differences in critical disease-associated phenotypes in individuals with DS. Autophagy is the process by which cellular material is recycled via the lysosome, and deficits in autophagy are thought to contribute to many of the diseases for which people with DS are at enhanced risk. Importantly, it is known that T21 causes impairment of autophagy; however it has not been addressed whether and how autophagy impairment contributes to specific manifestations of disease in people with DS. To test our hypothesis, we will test if variable deficits in autophagy in DS results in enhanced clonal hematopoiesis (CH). CH was chosen for this study because it is a specific, quantifiable disease phenotype that has major effects on health and which can be readily monitored in humans and mice from peripheral blood. We recently found that some but not all children with DS display enhanced CH (as seen in the typical elderly population) that is temporally related to their >50-fold increase in risk for childhood leukemia. This provides a strong rational for us to test our hypothesis in human samples and scientifically rigorous mouse models with two aims.
Aim 1 will determine the quantitative relationship between basal autophagic flux and clonal hematopoiesis in DS by leveraging a unique resource- the Human Trisome Project. This will allow us to perform what we believe will be the largest and most comprehensive analysis of the relationship between autophagy and any disease state in the Down Syndrome population.
Aim 1 will also determine the molecular mechanisms that underlie the deficit in autophagy that is caused by T21.
In Aim 2, we will test the requirement and sufficiency of autophagy variation/deficiency to explain enhanced clonal hematopoiesis using state of the art mouse models of DS and models that allow us to specifically manipulate autophagy. Additionally, we will test if interventions (exercise and a dietary supplement that has been shown to be safe in people and mice) designed to restore autophagy can reduce the risk of CH and protect against one of its more serious consequences, i.e. leukemia. Impact: our work may explain why severity of disease varies widely amongst individuals with DS. More important if it is feasible to restore autophagy in individuals with DS using relatively benign interventions and thus reduce CH, this will provide a framework to intervene to reduce risk of disease in people with DS.
Although everyone with Down Syndrome (DS) has an extra copy of chromosome 21, each individual with DS experiences differences in disease susceptibility and severity. One example is the expansion of mutated blood stem cells that can eventually lead to leukemia, seen in only some children with DS. Here we test if the reason for these differences is variation in a cellular recycling program called autophagy, which is essential for promoting overall health in multiple tissues and is impaired in people with DS. We will also test if it is possible to restore autophagy in mouse models of DS by exercise and dietary supplementation and if this can block the expansion of the mutated stem cells. This study may provide a framework for manipulating an entirely different biological process in order to reduce the risk of disease that is associated with the extra chromosome 21 that defines DS.
