ERC FUNDED PROJECTS

Atmospheric aerosol particles are a major player in the earth system: they impact the climate by scattering and absorbing solar radiation, as well as regulating the properties of clouds. On regional scales aerosol particles are among the main pollutants deteriorating air quality. Capturing the impact of aerosols is one of the main challenges in understanding the driving forces behind changing climate and air quality. Atmospheric aerosol numbers are governed by the ultrafine (< 100 nm in diameter) particles. Most of these particles have been formed from atmospheric vapours, and their fate and impacts are governed by the mass transport processes between the gas and particulate phases. These transport processes are currently poorly understood. Correct representation of the aerosol growth/shrinkage by condensation/evaporation of atmospheric vapours is thus a prerequisite for capturing the evolution and impacts of aerosols. I propose to start a research group that will address the major current unknowns in atmospheric ultrafine particle growth and evaporation. First, we will develop a unified theoretical framework to describe the mass accommodation processes at aerosol surfaces, aiming to resolve the current ambiguity with respect to the uptake of atmospheric vapours by aerosols. Second, we will study the condensational properties of selected organic compounds and their mixtures. Organic compounds are known to contribute significantly to atmospheric aerosol growth, but the properties that govern their condensation, such as saturation vapour pressures and activities, are largely unknown. Third, we aim to resolve the gas and particulate phase processes that govern the growth of realistic atmospheric aerosol. Fourth, we will parameterize ultrafine aerosol growth, implement the parameterizations to chemical transport models, and quantify the impact of these condensation and evaporation processes on global and regional aerosol budgets.

1 498 099 €

Start date: 2011-09-01, End date: 2016-08-31

My objective is to understand the physiologic and medical importance of the posttranslational processing of CAAX proteins (e.g., K-RAS and prelamin A) and to define the suitability of the CAAX protein processing enzymes as therapeutic targets for the treatment of cancer and progeria. CAAX proteins undergo three posttranslational processing steps at a carboxyl-terminal CAAX motif. These processing steps, which are mediated by four different enzymes (FTase, GGTase-I, RCE1, and ICMT), increase the hydrophobicity of the carboxyl terminus of the protein and thereby facilitate interactions with membrane surfaces. Somatic mutations in K-RAS deregulate cell growth and are etiologically involved in the pathogenesis of many forms of cancer. A mutation in prelamin A causes Hutchinson-Gilford progeria syndrome—a pediatric progeroid syndrome associated with misshaped cell nuclei and a host of aging-like disease phenotypes. One strategy to render the mutant K-RAS and prelamin A less harmful is to interfere with their ability to bind to membrane surfaces (e.g., the plasma membrane and the nuclear envelope). This could be accomplished by inhibiting the enzymes that modify the CAAX motif. My Specific Aims are: (1) To define the suitability of the CAAX processing enzymes as therapeutic targets in the treatment of K-RAS-induced lung cancer and leukemia; and (2) To test the hypothesis that inactivation of FTase or ICMT will ameliorate disease phenotypes of progeria. I have developed genetic strategies to produce lung cancer or leukemia in mice by activating an oncogenic K-RAS and simultaneously inactivating different CAAX processing enzymes. I will also inactivate several CAAX processing enzymes in mice with progeria—both before the emergence of phenotypes and after the development of advanced disease phenotypes. These experiments should reveal whether the absence of the different CAAX processing enzymes affects the onset, progression, or regression of cancer and progeria.

1 689 600 €

Start date: 2008-06-01, End date: 2013-05-31

This project aims to (i) resolve challenging graph problems in distributed and dynamic settings, with a focus on connectivity problems (such as computing edge connectivity and distances), and (ii) on the way develop a systematic approach to attack problems in these settings, by thoroughly exploring relevant algorithmic and complexity-theoretic landscapes. Tasks include - building a hierarchy of intermediate computational models so that designing algorithms and proving lower bounds can be done in several intermediate steps, - explaining the limits of algorithms by proving conditional lower bounds based on old and new reasonable conjectures, and - connecting techniques in the two settings to generate new insights that are unlikely to emerge from the isolated viewpoint of a single field. The project will take advantage from and contribute to the developments in many young fields in theoretical computer science, such as fine-grained complexity and sublinear algorithms. Resolving one of the connectivity problems will already be a groundbreaking result. However, given the approach, it is likely that one breakthrough will lead to many others.

1 500 000 €

Start date: 2017-02-01, End date: 2022-01-31

FateMapB aims to understand how the unique differentiation potential of fetal hematopoietic stem and progenitor cells (HSPCs) contribute to functionally distinct cell types of the adult immune system. While most immune cells are replenished by HSPCs through life, others emerge during a limited window in fetal life and sustain through self-renewal in situ. The lineage identity of fetal HSPCs, and the extent of their contribution to the adult immune repertoire remain surprisingly unclear. I previously identified the fetal specific RNA binding protein Lin28b as a post-transcriptional molecular switch capable of inducing fetal-like hematopoiesis in adult bone marrow HSPCs (Yuan et al. Science, 2012). This discovery has afforded me with unique perspectives on the formation of the mammalian immune system. The concept that the mature immune system is a mosaic of fetal and adult derived cell types is addressed herein with an emphasis on the B cell lineage. We will use two complementary lineage-tracing technologies to stratify the immune system as a function of developmental time, generating fundamental insight into the division of labor between fetal and adult HSPCs that ultimately provides effective host protection. Aim 1. Determine the qualitative and quantitative contribution of fetal HSPCs to the mature immune repertoire in situ through Cre recombination mediated lineage-tracing. Aim 2. Resolve the disputed lineage relationship between fetal derived B1a cells and adult derived B2 cells by single cell lineage-tracing using cellular barcoding in vivo. Aim 3. Characterize the mechanism and effector functions of Lin28b induced B1a cell development for assessing the clinical utility of inducible fetal-like lymphopoiesis. The implications of FateMapB extend beyond normal development to immune regeneration and age-related features of leukemogenesis. Finally, our combinatorial lineage-tracing approach enables dissection of cell fates with previously unattainable resolution.

1 499 905 €

Start date: 2017-10-01, End date: 2022-09-30