T lymphocytes play a central role in the immune defense against intruders, and support tissue homeostasis and function. Strikingly, an aged or dysfunctional T cell immunity is sufficient to promote organ aging and multiple age-related morbidities. In this proposal we hypothesize that there is a bidirectional relationship between T cells and their in vivo microenvironment that could develop into a vicious cycle under conditions of aging and disease. While a lot is known about the cellular mechanisms underlying T cell dysfunction with age, A profound understanding of how aging of the microenvironment impacts T cell immunity is missing. This work directly targets this gap to determine how the in vivo microenvironment in an aged mouse dictates T cells aging trajectories. Following on our preliminary findings, we will study two major mechanisms: (1) deficient metabolic support: we propose novel mechanisms by which stromal cells in the T cell zone of secondary lymphoid organs provide T cells metabolic needs for activation, and its failure in aged lymph nodes; and (2) toxic signals specific to the aged spleen that inhibit T cell metabolism and activation. Finally, we will investigate whether targeting these pathways would rejuvenate T cell immunity in vivo. The proposed study will discover unknown mechanisms supporting T cells metabolism in situ and will provide a causative link between T cell aging phenotypes and aging of their microenvironment. Finding new ways to rejuvenate immunity holds the promise for comprehensive and simultaneous targeting of multiple age-related pathologies.

Facial reconstruction usually involves the use of autologous grafts or composite tissue allografts, which are highly complex tissues that pose significant challenges to tissue engineering experts. Tissue engineering of independent facial elements, e.g., bone, adipose, skin and muscle tissues, has been demonstrated. However, to date, no composite soft tissues composed of multiple facial layers have been created. Composite facial tissue engineering will require proper innervation and vascularization, essential to support generation of large thick implants. However, techniques for effective innervation of engineered tissues are currently insufficient and generation of well-vascularized large and thick engineered tissues is still one of the major obstacles limiting their translation to the clinic. Our goal is to engineer thick, composite, human-scale, facial tissues (muscle-adipose-dermis composite, and bone) of a personally adaptable shape, that will be vascularized in-vitro, and innervated upon transplantation. Our concept is to create in-vitro a functional vascular network (VesselNet), composed of both large and small vessels, within engineered constructs, which will allow for the generation of thick engineered tissues under continuous flow conditions. 3D bio-printing techniques will be applied to create the engineered tissues. These tissues will serve as a model to study mechanisms involved in vessel anastomosis, and tissue organization and stabilization. The applicability of the engineered composite soft and bone tissues will be evaluated in facial, breast and abdominal wall defect reconstruction models, and in an open fracture model. Such engineered large-scale composite tissues are expected to have a major impact on reconstructive surgery and will shed light on yet unknown tissue organization mechanisms.

Despite that C–H functionalization represents a paradigm shift from the standard logic of organic synthesis, the selective activation of non-functionalized alkanes has puzzled chemists for centuries and is always referred to one of the remaining major challenges in chemical sciences. Alkanes are inert compounds representing the major constituents of natural gas and petroleum. Converting these cheap and widely available hydrocarbon feedstocks into added-value intermediates would tremendously affect the field of chemistry. For long saturated hydrocarbons, one must distinguish between non-equivalent but chemically very similar alkane substrate C−H bonds, and for functionalization at the terminus position, one must favor activation of the stronger, primary C−H bonds at the expense of weaker and numerous secondary C-H bonds. The goal of this work is to develop a general principle in organic synthesis for the preparation of a wide variety of more complex molecular architectures from saturated hydrocarbons. In our approach, the alkane will first be transformed into an alkene that will subsequently be engaged in a metal-catalyzed hydrometalation/migration sequence. The first step of the sequence, ideally represented by the removal of two hydrogen atoms, will be performed by the use of a mutated strain of Rhodococcus. The position and geometry of the formed double bond has no effect on the second step of the reaction as the metal-catalyzed hydrometalation/migration will isomerize the double bond along the carbon skeleton to selectively produce the primary organometallic species. Trapping the resulting organometallic derivatives with a large variety of electrophiles will provide the desired functionalized alkane. This work will lead to the invention of new, selective and efficient processes for the utilization of simple hydrocarbons and valorize the synthetic potential of raw hydrocarbon feedstock for the environmentally benign production of new compounds and new materials.