ProjectAbstract Biological networks organize specific chemical reactions in space and time. In cell signaling, scaffold proteins coordinate the formation of physical complexes that link multiple signaling proteinstogether.Thesescaffoldproteinshavemanyfunctionalroles:theycanrecruitproteinsto particular subcellular locations, serve as platforms to recruit regulatory factors, and direct pathwaystospecificoutputs.Scaffoldproteinsarealsothoughttoacceleratespecificbiochemical reactionswhenenzymesandproteinsarebroughttogethertothesamespatiallocation.Similar spatial organizing principles are involved in genome regulation, where the 3D structure of the genomeappearstoplayaregulatoryfunctionbypositioninggenesinproximitytoremoteDNA regulatorysitesortolocalizedproteins.Again,physicalproximityisthoughttopromotespecific biochemical processes in gene regulation. While there is extensive evidence that spatial organizationisimportantforbiologicalfunction,welackaquantitativeframeworktounderstand howenzymeactivitiesandotherbiochemicalfunctionsareaffectedbyspatialorganization.This gapinourknowledgemustbeaddressedtounderstandfundamentalprocesseslikecellsignaling andgeneregulation,andtointervenetherapeuticallywhentheseprocessesaremisregulated.To address this challenge, I propose to develop new tools to systematically perturb structural organization both in cell signaling networks and in the genome. I plan to use these tools to understand the underlying mechanistic principles that enable cells to control biochemical reactionswithincrediblespatialandtemporalprecision.
Biologicalnetworksareoftenspatiallyorganizedtoensurethatreactionsoccurattherightplace and time inside cells, particularly in fundamental processes like cell signaling and genome organization. We will develop tools to systematically perturb the relative spatial positions of biomolecules involved in these reaction networks, and to assess the functional consequences. Thisapproachwillenableustounderstandunderlyingregulatoryprinciplesandhowtointervene whentheseprocessesaremisregulatedinhumandiseases.
