ERC FUNDED PROJECTS

The unique manipulative abilities of the human hand have fascinated scientists since the time of Darwin. However, we know little about how these unique abilities evolved because we have lacked, (1) the necessary fossil human (hominin) evidence and (2) the appropriate methods to investigate if, when and how our early ancestors used their hands for locomotion (climbing) and manipulation (tool-use). The GRASP project will use novel morphological, experimental and biomechanical methods to investigate different locomotor and manipulative behaviours in humans and other apes, and will use this knowledge to reconstruct hand use in the most complete early hominin hand fossils, those of Australopithecus sediba. The goal of GRASP is to determine the evolutionary history of the human hand by addressing two fundamental, yet unresolved, questions: (1) Were our fossil hominin ancestors still using their hands for climbing? (2) When and in which fossil hominin species did stone tool-use and tool-making first evolve? These questions will be addressed via three objectives: First, microtomography and a novel, holistic method (MedTool®) will be used to analyse the internal bony structure of human, ape and fossil hominin hand bones. Second, collection of the necessary biomechanical data on (a) the loads experienced by the human hand during tool-use and tool-making, (b) hand use and hand postures used by African apes during locomotion in the wild and, (c) the loads experienced by the bonobo hand during arboreal locomotion. Third, data from the first two objectives will be used to adapt musculoskeletal models of the human and bonobo hand and, through the creation of 3D biomechanical (finite-element) models, simulate natural loading of individual hand bones in humans, bonobos and fossil hominins. With this detailed understanding of hand function, we will determine how the locomotor and manipulative behaviours of Au. sediba and other early hominins shaped the evolution of the human hand.

1 618 253 €

Start date: 2014-03-01, End date: 2019-02-28

Whole genome duplication (WGD) occurs in all eukaryotic kingdoms and is implicated in organismal complexity, adaptation and speciation. WGD is an especially important force in plant evolution and domestication. Nevertheless, despite the evolutionary potential of WGD, a sudden duplication of all chromosomes poses challenges to key processes, especially the reliable segregation of chromosomes at meiosis. Nonetheless, nature reveals solutions: the many polyploid species with diploid-like meiosis show that difficulties can be overcome. However, the molecular basis of this is mysterious: only one causal gene has been cloned to date. Our work in autotetraploid Arabidopsis arenosa revealed clear WGD-associated selective sweeps on meiosis genes with roles in crossover regulation. Natural variation in at least one of these genes has a dramatic effect on meiotic chromosome pairing. Here we assess whether species that independently adapted to the challenges attending WGD evolved similar solutions, whether crossover regulation is a common target of WGD-associated adaptation and whether standing variation in diploid populations contributes to adaptation to WGD. Aims of this programme are to: 1) produce quality reference genome assemblies for Cardamine amara and Arabis pumila, both of which harbor extant intraspecific ploidy variation; 2) test for the repeatability of adaptation mechanisms to WGD by genome scanning both species as well as three other independent WGDs in Arabidopsis lyrata and Mimulus guttatus; and 3) determine the causes and consequences of divergence of meiosis genes using functional analyses. We will utilize diverse genetic, genomic, and cytological approaches to understand repeatability and constraint in the context of intense selection on a conserved process. Further, this will provide insight into how organisms adapt to the altered cellular environment following WGD, a prevalent ongoing force in evolution and in the domestication of globally important crops.

1 490 329 €

Start date: 2016-01-01, End date: 2021-12-31

Chronic inflammation may result from failure of the host response to engage pro-resolving pathways. The current treatment armamentarium for chronic inflammatory conditions may lead to immune suppression. Thus, identification of novel therapeutics that control inflammation without immune suppression will provide an attractive alternative approach. This is especially important since incidence of these conditions increases with an ageing global population. In planaria, mice, human peripheral blood and milk I recently uncovered a new family of endogenous molecules, named Maresin Conjugates in Tissue Regeneration (MCTR). These potently regulate white blood cell responses, promote the resolution of acute inflammation and accelerate tissue regeneration. The aim of this Starting Grant is to identify pathways that lead to failed resolution in inflammatory arthritis, as a prototypical chronic inflammatory condition. The hypothesis is that MCTR biosynthesis is dysregulated in inflammatory arthritis, leading to an unbridled host response, chronic inflammation and tissue destruction. This proposal will employ a multipronged approach to test this hypothesis by 1) Determining MCTR regulation in self-resolving and delayed-resolving arthritis; 2) Investigating the host protective and tissue regenerative actions of MCTRs in inflammatory arthritis; 3) Establishing the MCTR biosynthetic pathway and 4) Determining the regulation if its components during self-limited and delayed-resolving arthritis. Anticipated results will uncover novel pathways that become dysregulated during failed resolution. Results from this Starting Grant will also identify targets and new therapeutic approaches that will engage pro-resolution programs as well as tissue regeneration in conditions characterised by persistent inflammation and hence failed resolution. This will lay the basis for informed structure-activity based studies and the design of therapeutics for treatment of chronic inflammatory conditions.

1 964 303 €

Start date: 2016-03-01, End date: 2021-08-31

Pulmonary fibrosis is a multifaceted and fatal disease that includes damaged alveolar epithelial cells and disorganization of multiple stromal cells. Dysregulation of multicellular crosstalk between epithelial and stromal cells is likely to contribute to fibrosis. However, the precise way this tissue damage occurs is unknown. I hypothesize that impaired function of lung epithelial stem cell lead to alveolar epithelial damage in pulmonary fibrosis, and which may be caused by altered stromal/niche cells. Epithelial injury repair and regeneration in the adult lung is carried out by numerous epithelial stem/progenitor cells. Recently, I identified a crucial interaction between lung endothelial cells and lung stem cells during alveolar injury response, and demonstrated a new regulatory signalling pathway that operates in endothelial cells to support alveolar injury repair by driving alveolar lineage specification of stem cells. Importantly, introduction of endothelial-derived factors into the lung after fibrotic damage enhances alveolar regeneration and reduces pulmonary fibrosis. Given these results and unique my background knowledge, I will bring a new concept of stem cell-niche interactions in alveolar injury repair and pulmonary fibrosis. Using both in vivo murine and organoid culture, as well as human lung organoid culture systems, I will define 1) whether and how the fibrotic response affects lung stem cells and 2) how lung stem cells are regulated by endothelial cells that may comprise their respective niches during injury repair. 3) The mechanisms involved in the normal and pathological regulation of lung stem cells will be elucidated by determining secreted factors and regulatory signals endothelial cells confer through paracrine and direct physical interaction with stem cells. Insights gained from these studies will accelerate the development of novel and selective therapeutic approaches that directly target stem cells or their niches in pulmonary fibrosis.

1 499 272 €

Start date: 2016-05-01, End date: 2021-04-30