Project acronym LEUKEMIABARRIER
Project The Leukemia-Initiating Cell: Genetic Determinants, Escape Mechanisms and Ontogenic Influence
Researcher (PI) David Bryder
Host Institution (HI) LUNDS UNIVERSITET
Call Details Consolidator Grant (CoG), LS4, ERC-2013-CoG
Summary Acute myeloid leukemia (AML) is the most common malignant myeloid disorder in adults and strongly associated in incidence to advanced age. AML arises from immature hematopoietic progenitor cells via a sequential multistep process, but the nature of these steps remains to a large extent unknown. Therefore, while significant efforts have previously been invested in characterizing the molecular properties of late-stage AML, as diagnosed in patients, less information is available on the events that underlie leukemia initiation and progression. This includes the identity of potential mechanisms that restrict or eradicate developing leukemic cells; hurdles evaded at some point in time for AML to occur.
We have developed an inducible transgenic mouse model of AML that, when combined with high-resolution cell fractionation of primitive hematopoietic progenitor cells, offers a unique opportunity to track development of AML from the very first stages of cancer development. Using this, I propose to: 1) Identify and functionally validate molecular determinants that underlie why only some hematopoietic progenitor cells progress into AML, 2) To explore the extent and identity of immune surveillance/editing that accompany progression into AML, and 3) By building on my previous work on hematopoietic aging, to explore AML progression in the context of aging.
I anticipate the LEUKEMIABARRIER project to generate novel basic knowledge, not excluding with clinical relevance, with the potential to open up several new fields for further studies. This includes identification of novel cell-intrinsic regulators and immune responses, their underlying mechanisms, and their relationship to the increased incidence of AML with age.
Summary
Acute myeloid leukemia (AML) is the most common malignant myeloid disorder in adults and strongly associated in incidence to advanced age. AML arises from immature hematopoietic progenitor cells via a sequential multistep process, but the nature of these steps remains to a large extent unknown. Therefore, while significant efforts have previously been invested in characterizing the molecular properties of late-stage AML, as diagnosed in patients, less information is available on the events that underlie leukemia initiation and progression. This includes the identity of potential mechanisms that restrict or eradicate developing leukemic cells; hurdles evaded at some point in time for AML to occur.
We have developed an inducible transgenic mouse model of AML that, when combined with high-resolution cell fractionation of primitive hematopoietic progenitor cells, offers a unique opportunity to track development of AML from the very first stages of cancer development. Using this, I propose to: 1) Identify and functionally validate molecular determinants that underlie why only some hematopoietic progenitor cells progress into AML, 2) To explore the extent and identity of immune surveillance/editing that accompany progression into AML, and 3) By building on my previous work on hematopoietic aging, to explore AML progression in the context of aging.
I anticipate the LEUKEMIABARRIER project to generate novel basic knowledge, not excluding with clinical relevance, with the potential to open up several new fields for further studies. This includes identification of novel cell-intrinsic regulators and immune responses, their underlying mechanisms, and their relationship to the increased incidence of AML with age.
Max ERC Funding
1 999 714 €
Duration
Start date: 2014-07-01, End date: 2019-06-30
Project acronym METABASE
Project Metagenome and Bariatric Surgery - New Avenues to Treat Metabolic Disease
Researcher (PI) Gert Fredrik Bäckhed
Host Institution (HI) GOETEBORGS UNIVERSITET
Call Details Consolidator Grant (CoG), LS4, ERC-2013-CoG
Summary Obesity and associated metabolic diseases such as type 2 diabetes are increasing worldwide and are the result of complex gene-environment interactions. Recent studies indicate that socio-demographic and environmental factors are more important for disease development than genetics, and we and others have demonstrated that the gut microbiota can be considered an environmental factor that contributes to obesity. Effective treatment for obesity remains a challenge and bariatric surgery is the only available therapy that is proven to maintain weight loss. Intriguingly, bariatric surgery also improves glucose metabolism, but the underlying molecular mechanisms for this beneficial effect are unclear. An altered gut microbiota has been linked to metabolic diseases and pilot studies indicate that the gut microbiota is also altered upon bariatric surgery; these findings suggest that some of the improved metabolic features following bariatric surgery may be mediated by altered composition of the gut microbiota. The overall goal of this proposal is to integrate clinical research with mechanistic studies in mice to determine if and how the gut microbiota mediates the beneficial effects of bariatric surgery. We will define how bariatric surgery alters the gut metagenome in humans, both at a species and at a functional level. By transferring the fecal microbiota from these patients before and after surgery to germ-free mice, we will determine if an altered gut microbiota directly modulates host metabolism. Finally, we will establish surgical methods in germ-free mice to directly test whether the beneficial effects observed following surgery require a microbiota. Increased understanding of these mechanisms may provide the basis for non-surgical treatments based on supplementation of novel probiotics to treat metabolic diseases. Follow-up work in larger clinical cohorts may also indicate how patients can be stratified to determine who would benefit the most from bariatric surgery.
Summary
Obesity and associated metabolic diseases such as type 2 diabetes are increasing worldwide and are the result of complex gene-environment interactions. Recent studies indicate that socio-demographic and environmental factors are more important for disease development than genetics, and we and others have demonstrated that the gut microbiota can be considered an environmental factor that contributes to obesity. Effective treatment for obesity remains a challenge and bariatric surgery is the only available therapy that is proven to maintain weight loss. Intriguingly, bariatric surgery also improves glucose metabolism, but the underlying molecular mechanisms for this beneficial effect are unclear. An altered gut microbiota has been linked to metabolic diseases and pilot studies indicate that the gut microbiota is also altered upon bariatric surgery; these findings suggest that some of the improved metabolic features following bariatric surgery may be mediated by altered composition of the gut microbiota. The overall goal of this proposal is to integrate clinical research with mechanistic studies in mice to determine if and how the gut microbiota mediates the beneficial effects of bariatric surgery. We will define how bariatric surgery alters the gut metagenome in humans, both at a species and at a functional level. By transferring the fecal microbiota from these patients before and after surgery to germ-free mice, we will determine if an altered gut microbiota directly modulates host metabolism. Finally, we will establish surgical methods in germ-free mice to directly test whether the beneficial effects observed following surgery require a microbiota. Increased understanding of these mechanisms may provide the basis for non-surgical treatments based on supplementation of novel probiotics to treat metabolic diseases. Follow-up work in larger clinical cohorts may also indicate how patients can be stratified to determine who would benefit the most from bariatric surgery.
Max ERC Funding
2 000 000 €
Duration
Start date: 2014-11-01, End date: 2019-10-31
