ADENYLYL CYCLASE TYPE 9: REGULATION AND CARDIAC FUNCTION

Abnormalities in cardiac stress signaling underlie a number of cardiovascular diseases (e.g. arrhythmias and heart failure). Cardiac stress signaling pathways normally integrate signals from the sympathetic nervous system to promote efficient contraction and relaxation under stress. Sympathetic control through β-adrenergic stimulation is propagated by adenylyl cyclase (AC). AC synthesizes cyclic AMP (cAMP), an important second messenger that initiates signaling pathways to modulate physiological and pathophysiological functions of the heart, including the activation of PKA and subsequent phosphorylation of ion channels, contractile machinery, and stress response proteins that enhance cardiac function. Alterations of cAMP signaling occur in the failing heart and contribute to impaired function. Of the AC isoforms present in adult cardiomyocytes (AC 4, 5, 6, and 9), AC9 is the most divergent in sequence and understudied. The work presented in this dissertation sought to evaluate the direct regulatory properties of AC9 and explores roles for AC9 in heart. To clarify conflicting reports for AC9 regulation, proposed regulators were systematically evaluated, including G-proteins, protein kinases, and forskolin utilizing in vitro and cell based assays. Overall, I conclude that most G-proteins or protein kinases do not directly regulate AC9, except Gαs, in vitro. Although AC9 is forskolin insensitive alone, weak activation by forskolin in the presence of Gαs is possible. AC9 shows significant homodimerization and modest heterodimerization with AC5/6, which may account for the conflicting reports surrounding the regulation of this AC isoform. viii To study the role of AC9 in heart, a mouse model of AC9 genetic deletion was utilized. Although deletion of AC9 reduces less than 3% of total AC activity in heart, Yotiao-associated AC activity is eliminated. AC9-/- mice exhibit no structural abnormalities but show a significant bradycardia and alterations in Doppler echocardiography indicative of grade 1 diastolic dysfunction with preserved ejection fraction. Identification of novel AC9 binding partners, including the small heat shock protein 20 (Hsp20) and Popeye domain containing (Popdc) proteins may contribute to the underlying mechanisms of AC9-/- phenotypes. Collectively, this work suggests that AC9 forms distinct macromolecular complexes that contribute to local cAMP pools important for driving physiological function of the heart

Contact monoids and Stein cobordisms

Suppose S is a compact surface with boundary, and let g be a diffeomorphism of S which fixes the boundary pointwise. We denote by (M_{S,g},\xi_{S,g})$ the contact 3-manifold compatible with the open book (S,g). In this article, we construct a Stein cobordism from the contact connected sum (M_{S,h},\xi_{S,h}) # (M_{S,g},\xi_{S,g}) to (M_{S,hg},\xi_{S,hg}), for any two boundary-fixing diffeomorphisms h and g. This cobordism accounts for the comultiplication map on Heegaard Floer homology discovered in an earlier paper by the author, and it illuminates several geometrically interesting monoids in the mapping class group of S. We derive some consequences for the fillability of contact manifolds obtained as cyclic branched covers of transverse knots.Comment: 12 pages, 5 figure

Coercive force of thin magnetic films

Phenomenological model aids in understanding the mechanisms responsible for the easy-axis coercive force in thin magnetic films of NiFe, MnBi, and gadolinium iron garnet

Comultiplication in link Floer homology and transversely non-simple links

For a word w in the braid group on n-strands, we denote by T_w the corresponding transverse braid in the rotational symmetric tight contact structure on S^3. We exhibit a map on link Floer homology which sends the transverse invariant associated to T_{ws_i} to that associated to T_w, where s_i is one of the standard generators of B_n. This gives rise to a "comultiplication" map on link Floer homology. We use this to generate infinitely many new examples of prime topological link types which are not transversely simple.Comment: 16 pages, 10 figure

On the equivalence of contact invariants in sutured Floer homology theories

We recently defined an invariant of contact manifolds with convex boundary in Kronheimer and Mrowka's sutured monopole Floer homology theory. Here, we prove that there is an isomorphism between sutured monopole Floer homology and sutured Heegaard Floer homology which identifies our invariant with the contact class defined by Honda, Kazez and Mati\'c in the latter theory. One consequence is that the Legendrian invariants in knot Floer homology behave functorially with respect to Lagrangian concordance. In particular, these invariants provide computable and effective obstructions to the existence of such concordances. Our work also provides the first proof which does not rely on the relative Giroux correspondence that the vanishing or non-vanishing of Honda, Kazez and Mati\'c's contact class is a well-defined invariant of contact manifolds.Comment: 63 pages, 13 figures; v2: corrected Lemma 3.3 and subsequent material, many other small changes; v3: accepted version, substantially revised to correct the proof of the main theore