ERC FUNDED PROJECTS

Dendritic cell (DC) activation and homing from the periphery to lymph nodes is a critical first event in the immune response. It involves upregulation of the chemokine receptor CCR7 and chemoinvasion towards lymphatic vessels. Despite its critical importance in adaptive immunity, the mechanisms of DC migration towards and entry into lymphatics are still poorly understood; this severely limits new therapeutic strategies for immunomodulation and even strategies for treating lymphedema, which is exacerbated by poor immune functioning. We propose a battery of physiological, cell-biological, molecular, and computational studies to determine both the mechanisms of DC homing to lymphatic vessels and how DCs modulate lymphatic function. We approach this from the perspectives of both the DC and the lymphatic vessel. Regarding the DC, we will examine computationally and experimentally how draining flows toward the lymphatic alter their migration tactics and test our hypothesis that DCs possess a biomolecular flow-detector network (which we refer to as autologous chemotaxis) and are thus able to sense the direction of the subtle flow of fluid toward the lymphatics. Regarding the lymphatic vessel, we will elucidate how biochemical and biophysical inflammatory signals regulate their drainage function, alter cell-cell adhesions and overall permeability, and alter adhesion receptors to facilitate DC homing and entry. Finally, we will examine DC migration in mice with dysfunctional lymphatics and explore strategies to improve immune response. These will be carried out in 4 main projects, and will complement our recent work in lymphatic functional biology as well as our more therapeutic investigations in DC targeting and activation (Reddy et al., Nature Biotechnol., 2007). This deeper knowledge of mechanisms of DC-lymphatic cross-talk in a relevant biophysical context will enable our long-term goal of rational design for therapeutic immunomodulation and lymphedema.

1 730 966 €

Start date: 2008-05-01, End date: 2013-04-30

One of the most challenging topics in modern number theory is the mysterious relation between special values of L-functions and Galois cohomology: they are the “shadows” in the two completely different worlds of complex and p-adic analysis of one and the same geometric object, viz the space of solutions for a given diophantine equation over the integral numbers, or more generally a motive M. The main idea of Iwasawa theory is to study manifestations of this principle such as the class number formula or the Birch and Swinnerton Dyer Conjecture simultaneously for whole p-adic families of such motives, which arise e.g. by considering towers of number fields or by (Hida) families of modular forms. The aim of this project is to supply further evidence for I. the existence of p-adic L-functions and for main conjectures in (non-commutative) Iwasawa theory, II. the (equivariant) epsilon-conjecture of Fukaya and Kato as well as III. the 2-variable main conjecture of Hida families. In particular, we hope to construct the first genuine “non-commutative” p-adic L-function as well as to find (non-commutative) examples fulfilling the expectation that the epsilon-constants, which are determined by the functional equations of the corresponding L-functions, build p-adic families themselves. In the third item a systematic study of Lie groups over pro-p-rings and Big Galois representations is planned with applications to the arithmetic of Hida families.

500 000 €

Start date: 2008-07-01, End date: 2013-06-30

I propose to initiate research on a specific group of bacteria, here denominated as the “Dehalococcoides-like Chloroflexi”. This group of bacteria is formed by several cultivated strains of the genus Dehalococcoides and many sequences of uncultivated organisms mostly from marine sediment or subsurface locations. All together form one subphylum of the Chloroflexi. Bacteria of the Dehalococcoides-like Chloroflexi are of particular importance for two independent reasons: first, the subphylum contains all bacteria known to transform under anaerobic conditions toxic and persistent halogenated compounds such as chlorinated dioxins, benzenes, biphenyls, vinyl chloride or brominated biphenylethers; secondly, massive amounts of Dehalococcoides-like Chloroflexi have recently been detected in marine organic-rich deep sediments dominating the populations with up to 80% of the total cell counts. However, many aspects of the physiology of Dehalococcoides species are unclear and almost nothing is known about Chloroflexi in deep sediments. I have worked for many years on the microbiology, biochemistry and genomics of Dehalococcoides species. With the proposed group I plan to focus on the physiological links between Chloroflexi in contaminated aquifers and those in marine sediments. Initially, cultures of marine sediment-Chloroflexi will be established in our lab and compared with pure Dehalococcoides strains. Objectives of our research towards marine Chloroflexi will be the description of the physiology, of the biochemistry of energy conservation and of key genes encoded in the genomes. It is anticipated that the research leads to a substantiated hypothesis on the mode of energy fixation in marine deep-sediments and an initial description of the role of Dehalococcoides-like Chloroflexi in biogeochemical cycles. We also expect to find insights into Chloroflexi evolution and their role in earth history by comparing genomes between Dehalococcoides species and marine Chloroflexi.

1 287 258 €

Start date: 2008-06-01, End date: 2013-12-31